73 results on '"Hůlková, H"'
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2. Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy
- Author
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Vylet’al, P., Hůlková, H., Živná, M., Berná, L., Novák, P., Elleder, M., and Kmoch, S.
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- 2008
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3. Lactosylceramide in lysosomal storage disorders. A comparative immunohistochemical and biochemical study
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Hůlková, H., Ledvinová, J., Asfaw, B., Koubek, K., Kopřiva, K., and Elleder, M.
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- 2005
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4. Expression and lysosomal targeting of CLN7, a major facilitator superfamily transporter associated with variant late-infantile neuronal ceroid lipofuscinosis
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Sharifi, A., Kousi, M., Sagné, C., Bellenchi, G.C., Morel, L., Darmon, M., Hůlková, H., Ruivo, R., Debacker, C., El Mestikawy, S., Elleder, M., Lehesjoki, A.-E., Jalanko, A., Gasnier, B., and Kyttälä, A.
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- 2010
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5. Alterations of uromodulin biology: A common denominator of the genetically heterogeneous FJHN/MCKD syndrome
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Vylet'al, P, Kublová, M, Kalbáčová, M, Hodaňová, K, Barešová, V, Stibůrková, B, Sikora, J, Hůlková, H, Živný, J, Majewski, J, Simmonds, A, Fryns, J-P, Venkat-Raman, G, Elleder, M, and Kmoch, S
- Published
- 2006
6. OBOUSTRANNÁ AMYLOIDÓZA TŘÍ VÍČEK. KAZUISTIKA.
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Krásný, J., Šach, J., Hůlková, H., and Pavlíček, P.
- Published
- 2021
7. [Disorders of mitochondrial energy metabolism in patients with the Kearns-Sayre syndrome]
- Author
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Capková M, Tesarová M, Wenchich L, Cerná L, Hansíková H, Hůlková H, Hrubá E, Elleder M, and Jiri Zeman
- Subjects
Adult ,Genetic Markers ,Male ,Adolescent ,Humans ,Female ,Kearns-Sayre Syndrome ,Energy Metabolism ,DNA, Mitochondrial ,Mitochondria, Muscle ,Sequence Deletion - Abstract
Kearns-Sayre syndrome is a multisystem disorder caused by rearrangements of mitochondrial genome including various deletions and/or duplications. The aim of the study is to analyse the impact of mitochondrial DNA (mtDNA) deletions on the mitochondrial energetic metabolism in five patients with Kearns-Sayre syndrome.The course of the disease is progressive in all patients. All of them have bilateral ptosis and external opthalmoplegia, four have retinitis pigmentosa, three have progressive muscle weakness and three have pacemaker because of complete A-V heart block. One patient underwent renal transplantation at the age of 12 because of a chronic renal failure. Southern blot analysis in muscle tissue revealed large scale heteroplasmic mtDNA deletions (3-7.4 kb) in all patients, the number of mutated copies of mtDNA ranged from 50 to 70%. Spectrophotometric measurements of respiratory chain complexes activities in muscle tissue revealed various combinations of defects of complex III, IV and I + III activities in all patients. Nevertheless, the lactic acidosis was permanently present only in one patient. Ragged-red fibers were found in two patients.Although the diagnostic of Kearns-Sayre syndrome is based on clinical features, molecular analysis of mtDNA is necessary to confirm the diagnosis. The prognosis of the disease is unfavourable and co-operation between the patient and various specialists is necessary for the treatment, which is currently only symptomatic.
- Published
- 2002
8. Histochemical detection of GM1 ganglioside using cholera toxin-B subunit. Evaluation of critical factors optimal for in situ detection with special emphasis to acetone pre-extraction
- Author
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Petr, T., primary, Šmíd, V., additional, Šmídová, J., additional, Hůlková, H., additional, Jirkovská, M., additional, Elleder, M., additional, Muchová, L., additional, Vitek, L., additional, and Šmíd, F., additional
- Published
- 2010
- Full Text
- View/download PDF
9. Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy
- Author
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Vylet'al, P., primary, Hůlková, H., additional, Živná, M., additional, Berná, L., additional, Novák, P., additional, Elleder, M., additional, and Kmoch, S., additional
- Published
- 2008
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10. Prosaposin Deficiency - a Rarely Diagnosed, Rapidly Progressing, Neonatal Neurovisceral Lipid Storage Disease. Report of a Further Patient
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Elleder, M., primary, Jeřábková, M., additional, Befekadu, A., additional, Hřebíček, M., additional, Berná, L., additional, Ledvinová, J., additional, Hůlková, H., additional, Rosewich, H., additional, Schymik, N., additional, Paton, B. C., additional, and Harzer, K., additional
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- 2005
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11. Nemoc ze střádání esterů cholesterolu (CESD): klinická, laboratorní a histologická charakteristika šesti pacientů.
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Mazurová, S., Poupětová, H., Hůlková, H., Ťoukálková, L., Urbanová, Z., Zeman, J., Smolka, V., Malinová, V., and Honzík, T.
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WOLMAN disease ,CHOLESTERYL ester transfer protein ,TRIGLYCERIDES ,LYSOSOMES ,HEPATIC fibrosis - Abstract
Copyright of Czecho-Slovak Pediatrics / Česko-Slovenská Pediatrie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2014
12. [Various manifestations of the A8344G mtDNA heteroplasmic mutation in 4 families with the MERRF syndrome]
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Stratilová L, Jiri Zeman, Houst'ková H, Hansíková H, Konrádová V, Hůlková H, Elleder M, Růzicka E, Tyl D, Hrubá E, and Houstĕk J
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Adult ,Aged, 80 and over ,Male ,Muscles ,Infant ,Middle Aged ,DNA, Mitochondrial ,Polymerase Chain Reaction ,MERRF Syndrome ,Pedigree ,Humans ,Point Mutation ,Female ,Child ,Aged - Abstract
The most frequent manifestation of mitochondrial DNA (mtDNA) mutation 8344 A--G is MERRF syndrome (Myoclonic Epilepsy and Myopathy with Ragged Red Fibres). Less frequent symptoms include ataxia, perceptive type of deafness, cardiomyopathy or external ophthalmoplegia and mental and motor retardation in children. We describe heterogeneity of clinical symptoms and results of biochemical and molecular investigations in four families with the heteroplasmic mutation 8344 A--G in mtDNA.In co-operation with paediatric, neurological and genetic specialists from the Czech and Slovak Republic we found in 1993-1998 at the enzymatic or molecular level more than 90 children and adults with impaired mitochondrial energy metabolism. Heteroplasmic mutation 8344 A--G in mtDNA was found in four families. Ataxia and progressive muscle weakness appeared in the first proband with 50% of mutated copies of mtDNA in muscle at the age of 30 years. The second proband with 95% of mutated mtDNA had his first clinical symptoms--muscle hypotonia, cardiomyopathy and mental and motor retardation--in infancy while his four relatives with 25-50% mutated mtDNA lack so far clinical symptoms. In a female from the third family with 50% mutated mtDNA in muscle the disease manifested at the age of 42 years with progressive external ophthalmoplegia (PEO) and muscle weakness. In the fourth proband with 50% of mutated mtDNA in blood the disease started in infancy with spastic quadruparesis and arrested mental and motor development. Enzymatic and histochemical investigation in muscle biopsy in two probands revealed lower cytochrom c oxidase activity. Ragged-red fibres were found only in one adult patient.MtDNA mutation 8344 A--G can manifest by heterogeneous symptoms. A higher percentage of mutated mtDNA is usually associated with more serious forms of the disease, but there is not always a correlation between the degree of heteroplasmy and severity of the disease or the age of the first clinical symptoms.
13. Disorders of mitochondrial energy metabolism in patients with the Kearns-Sayre syndrome | Poruchy mitochondriálního energetického metabolizmu u pacientů s Kearns-Sayreovým syndromem
- Author
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Capková, M., Tesarová, M., Wenchich, L., Cerná, L., Hansíková, H., Hůlková, H., Hrubá, E., Elleder, M., and Jiri Zeman
14. Histopathological diagnosis of mitochondrial myopathies - Indications and the utility of muscle biopsy | Histopatologická diagnostika mitochondriálních myopatií - Indikace a přínos svalové biopsie
- Author
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Souček, O., Ješina, P., Jiri Zeman, Elleder, M., Hůlková, H., and Lukáš, Z.
15. Mitochondrial myopathy, deafness and type 2 diabetes mellitus with tRNALeu(UUR) point mutation in mitochondrial DNA | Mitochondriální myopatie, hluchota a diabetes mellitus 2. typu na podklade bodové mutace tRNALeu(UUR) v mitochondriální DNA
- Author
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Stratilová, L., Jiri Zeman, Hansíková, H., Houstek, J., Hermanská, J., Dudková, Z., Konrádová, V., Hůlková, H., and Elleder, M.
16. [Postmortem diagnosis of Fabry disease in a female heterozygote leading to the detection of undiagnosed manifest disease in the family]
- Author
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Hůlková H, Ledvinová J, Poupĕtová H, Bultas J, Jiri Zeman, and Elleder M
- Subjects
Adult ,Male ,Heterozygote ,Adolescent ,Fabry Disease ,Humans ,Female ,Autopsy ,Middle Aged ,Pedigree - Abstract
The authors detected on necropsy in a 63-year-old woman with the clinical diagnosis of hypertension, atherosclerosis of the coronary and peripheral arteries, thromboembolism into the cerebral circulation and impaired cardiac conductivity lysosomal storage identified by histochemical and electronoptic analyses along with lipid chromatography as Fabry's disease. The stored lipids were neutral glycosphingolipids of the globo series globotriaosylceramide) and of the gala- series (galabiosylceramide) which accumulated as a result of deficient activity of the degrading enzyme alpha galactosidase A. Marked accumulation of these specific lipids was found in cardiomyocytes, in smooth muscles (of the media in arteries of the heart, kidneys, liver, spleen, lungs) in podocytes and mesangial cells of renal glomeruli, in epithelia of Henle's loop and in the distal tubules. In the vascular endothelium the storage was at the borderline of detectability. Accumulation did not lead to detectable organ disorders with the exception of the heart where it participated, no doubt, significantly in the cardiocyte hypertrophy. Examination of relatives revealed in the proband's son (age 41 years) a combination of renal, cardiac and skin changes typical for Fabry's disease which, however was not clinically diagnosed. The diagnosis was confirmed by proving of alpha-galactosidase A deficiency in the peripheral leucocytes and point mutation L293X in the VIth exon of the appropriate gene. In a granddaughter (age 15 years) biochemical and molecular genetic methods revealed the heterozygous state of Fabry's disease in preclinical stage.
17. Disorders of mitochondrial energy metabolism in patients with the Kearns-Sayre syndrome,Poruchy mitochondriálního energetického metabolizmu u pacientů s Kearns-Sayreovým syndromem
- Author
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Capková, M., Tesarová, M., László Wenchich, Cerná, L., Hansíková, H., Hůlková, H., Hrubá, E., Elleder, M., and Zeman, J.
18. Postmortem diagnosis of Fabry disease in a female heterozygote leading to the detection of undiagnosed manifest disease in the family | Pitevní diagnóza Fabryho nemoci u heterozygotky, vedoucí k rozpoznání nediagnostikované manifestní nemoci v rodine
- Author
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Hůlková, H., Ledvinová, J., Poupětová, H., Bultas, J., Jiri Zeman, and Elleder, M.
19. [Mitochondrial myopathy, deafness and type 2 diabetes mellitus with tRNALeu(UUR) point mutation in mitochondrial DNA]
- Author
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Stratilová L, Jiri Zeman, Hansíková H, Houstĕk J, Hermanská J, Dudková Z, Konrádová V, Hůlková H, and Elleder M
- Subjects
Diabetes Mellitus, Type 2 ,MELAS Syndrome ,Humans ,Mitochondrial Myopathies ,Point Mutation ,Female ,Deafness ,Middle Aged ,DNA, Mitochondrial - Abstract
A heteroplasmic A3243G point mutation in tRNALeu(UUR) gene of mitochondrial DNA (mtDNA) is found in patients with MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes), less frequently in patients with other dominating clinical features, such as deafness, diabetes mellitus type 2, hypertrophic cardiomyopathy, renal problems or inborn development defects. Present report describes histochemical, enzymatic and molecular biology studies of the family with clinical variant of meals syndrome.A 45-year-old woman with progressive muscle weakness, external ophtalmoplegia, perceptive deafness, ischemic heart disease, diabetes mellitus type 2 and hyperlactacidemia was metabolically investigated because the multiorgan problems indicated mitochondrial origin of the disease. Muscle biopsy revealed pronounced myopathic changes, ragged red fibers and decreased activity of respiratory chain enzymes - succinate cytochrome c reductase (5% control) and cytochrome c oxidase (10% control). Restriction fragment analysis of mtDNA from muscle, blood and hair follicles detected heteroplasmic A -G mutation in the position 3243 of the tRNALeu(UUR) gene, which was more pronounced in muscle (28% of total mtDNA) than in blood (12%) or in hair follicles (10%). No mutation was found in blood and hair follicles of patient's mother and daughter.Diagnostics of mitochondrial diseases require close collaboration of clinicians with specialised laboratories. Treatment of mitochondrial disorders is only symptomatic, however, early diagnosis of the molecular defect is important for genetic counselling.
20. An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes
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Veronika Baresova, Miroslav Votruba, Kálmán Tory, Aleš Hnízda, Jakub Sikora, Matthias T.F. Wolf, Marisa Santostefano, Neila Belghith, Lídia Balogh, Jan Živný, Tal Kopel, Robert M. Haws, Bertrand Knebelmann, Andrea Wenzel, Bodo B. Beck, Lawrence R. Shoemaker, Laurent Mesnard, Anna Jakubowska, Kendrah Kidd, Charles Shaw-Smith, Christoforos Stavrou, Mayssa Abdelwahed, Constantinos Deltas, John A. Sayer, Claudio Graziano, Rhian L Clissold, Petr Vyleťal, Stanislav Kmoch, Victoria Robins, Howard Trachtman, Michael E. Bleyer, Marie Matignon, Anthony J. Bleyer, Kathleen Claes, Jana Sovová, Irene Capelli, Philippe Grimbert, Sharon M. Moe, Luca Rampoldi, Ivana Jedličková, Karsten Häeffner, Stéphane Decramer, Kateřina Hodaňová, Helena Trešlová, Matthew R. Sinclair, Raj Munshi, Gregory Papagregoriou, Hana Hartmannová, Albert C.M. Ong, Mohamad Zaidan, Agnieszka Łaszkiewicz, Amy N. Sussman, Claudia Izzi, Martina Živná, Helena Hůlková, Francesco Scolari, Živná, M, Kidd, K, Zaidan, M, Vyleťal, P, Barešová, V, Hodaňová, K, Sovová, J, Hartmannová, H, Votruba, M, Trešlová, H, Jedličková, I, Sikora, J, Hůlková, H, Robins, V, Hnízda, A, Živný, J, Papagregoriou, G, Mesnard, L, Beck, Bb, Wenzel, A, Tory, K, Häeffner, K, Wolf, Mtf, Bleyer, Me, Sayer, Ja, Ong, Acm, Balogh, L, Jakubowska, A, Łaszkiewicz, A, Clissold, R, Shaw-Smith, C, Munshi, R, Haws, Rm, Izzi, C, Capelli, I, Santostefano, M, Graziano, C, Scolari, F, Sussman, A, Trachtman, H, Decramer, S, Matignon, M, Grimbert, P, Shoemaker, Lr, Stavrou, C, Abdelwahed, M, Belghith, N, Sinclair, M, Claes, K, Kopel, T, Moe, S, Deltas, C, Knebelmann, B, Rampoldi, L, Kmoch, S, and Bleyer, Aj
- Subjects
0301 basic medicine ,Signal peptide ,Adult ,Male ,medicine.medical_specialty ,Mutant ,030232 urology & nephrology ,Chromosomal translocation ,autosomal dominant tubulointerstitial kidney disease ,characterization ,mutation ,prosegment ,renin ,signal peptide ,medicine.disease_cause ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Renin–angiotensin system ,Renin ,medicine ,Humans ,Secretion ,Child ,Mutation ,Polycystic Kidney Diseases ,business.industry ,Endoplasmic reticulum ,Anemia ,medicine.disease ,030104 developmental biology ,Endocrinology ,Nephrology ,Female ,business ,Kidney disease - Abstract
There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.
- Published
- 2020
21. A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis.
- Author
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Elhassan EAE, Kmochová T, Benson KA, Fennelly NK, Barešová V, Kidd K, Doyle B, Dorman A, Morrin MM, Kyne NC, Vyleťal P, Hartmannová H, Hodaňová K, Sovová J, Mušálková D, Vrbacká A, Přistoupilová A, Živný J, Svojšová K, Radina M, Stránecký V, Loginov D, Pompach P, Novák P, Vaníčková Z, Hansíková H, Rajnochová-Bloudíčková S, Viklický O, Hůlková H, Cavalleri GL, Hnízda A, Bleyer AJ, Kmoch S, Conlon PJ, and Živná M
- Abstract
Introduction: Monoallelic variants in the ALG5 gene encoding asparagine-linked glycosylation protein 5 homolog (ALG5) have been recently shown to disrupt polycystin-1 (PC1) maturation and trafficking via underglycosylation, causing an autosomal dominant polycystic kidney disease-like (ADPKD-like) phenotype and interstitial fibrosis. In this report, we present clinical, genetic, histopathologic, and protein structure and functional correlates of a new ALG5 variant, p.R79W, that we identified in 2 distant genetically related Irish families displaying an atypical late-onset ADPKD phenotype combined with tubulointerstitial damage., Methods: Whole exome and targeted sequencing were used for segregation analysis of available relatives. This was followed by immunohistochemistry examinations of kidney biopsies, and targeted (UMOD, MUC1) and untargeted plasma proteome and N-glycomic studies., Results: We identified a monoallelic ALG5 variant [GRCh37 (NM_013338.5): g.37569565G>A, c.235C>T; p.R79W] that cosegregates in 23 individuals, of whom 18 were clinically affected. We detected abnormal localization of ALG5 in the Golgi apparatus of renal tubular cells in patients' kidney specimens. Further, we detected the pathological accumulation of uromodulin, an N-glycosylated glycosylphosphatidylinositol (GPI)-anchored protein, in the endoplasmic reticulum (ER), but not mucin-1, an O- and N-glycosylated protein. Biochemical investigation revealed decreased plasma and urinary uromodulin levels in clinically affected individuals. Proteomic and glycoproteomic profiling revealed the dysregulation of chronic kidney disease (CKD)-associated proteins., Conclusion: ALG5 dysfunction adversely affects maturation and trafficking of N-glycosylated and GPI anchored protein uromodulin, leading to structural and functional changes in the kidney. Our findings confirm ALG5 as a cause of late-onset ADPKD and provide additional insight into the molecular mechanisms of ADPKD- ALG5 ., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)
- Published
- 2024
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- View/download PDF
22. Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.
- Author
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Kmochová T, Kidd KO, Orr A, Hnízda A, Hartmannová H, Hodaňová K, Vyleťal P, Naušová K, Brinsa V, Trešlová H, Sovová J, Barešová V, Svojšová K, Vrbacká A, Stránecký V, Robins VC, Taylor A, Martin L, Rivas-Chavez A, Payne R, Bleyer HA, Williams A, Rennke HG, Weins A, Short PJ, Agrawal V, Storsley LJ, Waikar SS, McPhail ED, Dasari S, Leung N, Hewlett T, Yorke J, Gaston D, Geldenhuys L, Samuels M, Levine AP, West M, Hůlková H, Pompach P, Novák P, Weinberg RB, Bedard K, Živná M, Sikora J, Bleyer AJ Sr, and Kmoch S
- Subjects
- Humans, Middle Aged, Mutation, Nephritis, Interstitial diagnosis, Nephritis, Interstitial genetics, Nephritis, Interstitial complications, Amyloidosis, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic complications, Apolipoproteins A
- Abstract
Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m
2 , including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2 . Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
23. Autosomal dominant tubulointerstitial kidney disease: A review.
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Živná M, Kidd KO, Barešová V, Hůlková H, Kmoch S, and Bleyer AJ Sr
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- Humans, Young Adult, Adult, Middle Aged, Aged, Uromodulin genetics, Mutation, Genetic Testing, Renal Insufficiency, Chronic
- Abstract
The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD-UMOD is also associated with hyperuricemia and gout. ADTKD-REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients., (© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)
- Published
- 2022
- Full Text
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24. BILATERAL AMYLOIDOSIS OF THREE EYELIDS. A CASE REPORT.
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Krásný J, Šach J, Hůlková H, and Pavlíček P
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- Aged, Biopsy, Czech Republic, Humans, Male, Amyloidosis complications, Amyloidosis diagnosis, Eyelids surgery
- Abstract
Aim: To present rare form of lids amyloidosis, in the context with literature and remind a Czech professor Vrabec, F., MD, an important pan-European ocular histologist., Case Report: 37 years aged man was examined for eyelids mass on the department of ophthalmology of the Teaching Hospital Kralovske Vinohrady, Prague, Czech Republic in June 2018. The finding looked like chronic chalazion on the right side and chronic hordeolum on the left side. No acute phase was noted within last several months by the patient. Yellowish to lightly brown friable, partially transparent mass was obtained by excision. Amyloidosis of the AL type was revealed histologically, and diagnosis was followed by extended excision and plastic surgical reconstruction of the lower eyelids on both sides. No systemic disease underlying the amyloidosis was disclosed by following through diagnostic work-up of the patient., Results: Amyloidosis was illustrated initially by Congo red staining with characteristic dichroism in the polarized light, then it was analysed immunohistochemically, with positivity for kappa light chains. Systemic amyloidosis was excluded, as well as monoclonal gamapathy. Only slightly increased number of plasmacytes (up to 10 %) was revealed in the bone marrow biopsy. The surgical solution was optimal for the patient, and he was without any recurrence and problems of lower eyelids three years., Conclusion: Described case of bilateral eyelids amyloidosis without underlying systemic disease belongs to rare cases and also illustrates necessity of complex interdisciplinary cooperation in the diagnostic process.
- Published
- 2021
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- View/download PDF
25. An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.
- Author
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Živná M, Kidd K, Zaidan M, Vyleťal P, Barešová V, Hodaňová K, Sovová J, Hartmannová H, Votruba M, Trešlová H, Jedličková I, Sikora J, Hůlková H, Robins V, Hnízda A, Živný J, Papagregoriou G, Mesnard L, Beck BB, Wenzel A, Tory K, Häeffner K, Wolf MTF, Bleyer ME, Sayer JA, Ong ACM, Balogh L, Jakubowska A, Łaszkiewicz A, Clissold R, Shaw-Smith C, Munshi R, Haws RM, Izzi C, Capelli I, Santostefano M, Graziano C, Scolari F, Sussman A, Trachtman H, Decramer S, Matignon M, Grimbert P, Shoemaker LR, Stavrou C, Abdelwahed M, Belghith N, Sinclair M, Claes K, Kopel T, Moe S, Deltas C, Knebelmann B, Rampoldi L, Kmoch S, and Bleyer AJ
- Subjects
- Adult, Child, Cohort Studies, Female, Humans, Male, Mutation, Renin genetics, Young Adult, Anemia, Polycystic Kidney Diseases genetics
- Abstract
There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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26. Long-term uninterrupted enzyme replacement therapy prevents liver disease in murine model of severe homocystinuria.
- Author
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Park I, Hůlková H, Krijt J, Kožich V, Bublil EM, and Majtan T
- Subjects
- Animals, Disease Models, Animal, Female, Liver pathology, Male, Mice, Mice, Knockout, Enzyme Replacement Therapy, Homocystinuria drug therapy, Liver Diseases prevention & control
- Abstract
Classical homocystinuria (HCU) is an inborn error of metabolism caused by loss of cystathionine β-synthase (CBS) activity with the concomitant buildup of homocysteine. In knockout (KO) mice, a mouse model of HCU, complete lack of CBS is neonatally lethal. Administration of OT-58, an enzyme therapy for HCU, during the first 5 weeks of life rescued KO mice survival by preventing liver disease. Here, we studied the impact of a long-term uninterrupted OT-58 treatment or its absence beyond the neonatal period on liver pathology and metabolism. Plasma and liver metabolites of KO mice on OT-58 treatment were substantially improved or normalized compared with those receiving vehicle. Increased plasma activities of alanine aminotransferase and aspartate aminotransferase of vehicle-injected KO mice suggested the progression of liver damage with age and lack of treatment. At 3 months of age, liver histology showed no signs of hepatopathy in both vehicle- and OT-58-treated KO mice. However, moderate to severe liver disease, characterized by steatosis, hepatocellular necroses, disorganized endoplasmic reticulum, and swollen mitochondria, developed in 6-month-old vehicle-injected KO mice. KO mice on OT-58 treatment remained asymptomatic and were indistinguishable from age-matched healthy controls. Long-term uninterrupted OT-58 treatment was essential to prevent severe liver disease in the KO mouse model of HCU., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
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27. Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing.
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Jedličková I, Cadieux-Dion M, Přistoupilová A, Stránecký V, Hartmannová H, Hodaňová K, Barešová V, Hůlková H, Sikora J, Nosková L, Mušálková D, Vyleťal P, Sovová J, Cossette P, Andermann E, Andermann F, and Kmoch S
- Subjects
- Adult, Animals, Cell Line, False Negative Reactions, Female, Genetic Testing standards, HSP40 Heat-Shock Proteins metabolism, Humans, Male, Membrane Proteins metabolism, Mice, Middle Aged, Neuronal Ceroid-Lipofuscinoses pathology, Neurons metabolism, Protein Processing, Post-Translational, Protein Transport, Whole Genome Sequencing standards, Gene Duplication, HSP40 Heat-Shock Proteins genetics, Membrane Proteins genetics, Neuronal Ceroid-Lipofuscinoses genetics
- Abstract
Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroid in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration. Although several causative genes have been identified (DNAJC5, CLN6, CTSF, GRN, CLN1, CLN5, ATP13A2), the genetic underpinnings of ANCL in some families remain unknown. Here we report one family with autosomal dominant (AD) Kufs disease caused by a 30 bp in-frame duplication in DNAJC5, encoding the cysteine-string protein alpha (CSPα). This variant leads to a duplication of the central core motif of the cysteine-string domain of CSPα and affects palmitoylation-dependent CSPα sorting in cultured neuronal cells similarly to two previously described CSPα variants, p.(Leu115Arg) and p.(Leu116del). Interestingly, the duplication was not detected initially by standard Sanger sequencing due to a preferential PCR amplification of the shorter wild-type allele and allelic dropout of the mutated DNAJC5 allele. It was also missed by subsequent whole-exome sequencing (WES). Its identification was facilitated by reanalysis of original WES data and modification of the PCR and Sanger sequencing protocols. Independently occurring variants in the genomic sequence of DNAJC5 encoding the cysteine-string domain of CSPα suggest that this region may be more prone to DNA replication errors and that insertions or duplications within this domain should be considered in unsolved ANCL cases.
- Published
- 2020
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28. Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease.
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Živná M, Kidd K, Přistoupilová A, Barešová V, DeFelice M, Blumenstiel B, Harden M, Conlon P, Lavin P, Connaughton DM, Hartmannová H, Hodaňová K, Stránecký V, Vrbacká A, Vyleťal P, Živný J, Votruba M, Sovová J, Hůlková H, Robins V, Perry R, Wenzel A, Beck BB, Seeman T, Viklický O, Rajnochová-Bloudíčková S, Papagregoriou G, Deltas CC, Alper SL, Greka A, Bleyer AJ, and Kmoch S
- Subjects
- Biopsy, Needle, Case-Control Studies, Female, Humans, Immunohistochemistry, Incidence, Male, Mutation genetics, Pedigree, Polycystic Kidney, Autosomal Dominant mortality, Prognosis, Registries, Retrospective Studies, Risk Assessment, Genetic Predisposition to Disease epidemiology, Mucin-1 genetics, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
Background: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene ( MUC1 ) mutations (ADTKD- MUC1 ) is characterized by progressive kidney failure. Genetic evaluation for ADTKD- MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein., Methods: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD- MUC1- positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations., Results: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein., Conclusions: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD- MUC1 ., (Copyright © 2018 by the American Society of Nephrology.)
- Published
- 2018
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29. Autosomal Dominant Tubulointerstitial Kidney Disease Due to MUC1 Mutation.
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Yu SM, Bleyer AJ, Anis K, Herlitz L, Živná M, Hůlková H, Markowitz GS, and Jim B
- Subjects
- Adult, Biopsy, DNA Mutational Analysis, Female, Humans, Mucin-1 metabolism, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant metabolism, Ultrasonography, DNA genetics, Kidney pathology, Mucin-1 genetics, Mutation, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Mucin 1 kidney disease, previously referred to as medullary cystic kidney disease type 1, is a rare hereditary kidney disease. It is one of several diseases now termed autosomal dominant tubulointerstitial kidney disease, as proposed by a KDIGO (Kidney Disease: Improving Global Outcomes) consensus report in 2014. Autosomal dominant tubulointerstitial kidney diseases share common clinical findings, such as autosomal dominant inheritance, bland urinary sediment, absent to mild proteinuria, and progressive loss of kidney function. Although the pathophysiology of mucin 1 kidney disease is still under investigation, genetic testing has been developed to detect the most well-known mutation, a single cytosine insertion into a string of 7 cytosines in the variable-number tandem repeat (VNTR) region of the MUC-1 gene. With this diagnostic tool, nephrologists can offer genetic counseling to affected families and monitor closely for progression of disease. We report a Hispanic patient with a strong family history of chronic kidney disease who tested positive for the MUC1 mutation., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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30. Teenage-onset progressive myoclonic epilepsy due to a familial C9orf72 repeat expansion.
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van den Ameele J, Jedlickova I, Pristoupilova A, Sieben A, Van Mossevelde S, Ceuterick-de Groote C, Hůlková H, Matej R, Meurs A, Van Broeckhoven C, Berkovic SF, Santens P, Kmoch S, and Dermaut B
- Subjects
- Adult, Age of Onset, Brain pathology, Family, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Myoclonic Epilepsies, Progressive pathology, Myoclonic Epilepsies, Progressive physiopathology, Myoclonic Epilepsies, Progressive psychology, Pedigree, Phenotype, C9orf72 Protein genetics, DNA Repeat Expansion, Myoclonic Epilepsies, Progressive genetics
- Abstract
Background: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously., Objective: To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME., Results: We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions., Conclusion: C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence., (© 2018 American Academy of Neurology.)
- Published
- 2018
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31. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria.
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Majtan T, Hůlková H, Park I, Krijt J, Kožich V, Bublil EM, and Kraus JP
- Subjects
- Animals, Body Composition drug effects, Cystathionine beta-Synthase genetics, Disease Models, Animal, Fatty Liver enzymology, Female, Homocystinuria metabolism, Homocystinuria pathology, Liver drug effects, Liver enzymology, Liver metabolism, Liver pathology, Liver Diseases enzymology, Male, Mice, Mice, Knockout, Recombinant Proteins therapeutic use, Cystathionine beta-Synthase metabolism, Cystathionine beta-Synthase therapeutic use, Fatty Liver prevention & control, Homocystinuria drug therapy, Homocystinuria enzymology, Liver Diseases prevention & control, Osteoporosis prevention & control
- Abstract
Classical homocystinuria (HCU) is an inborn error of sulfur amino acid metabolism caused by deficient activity of cystathionine β-synthase (CBS), resulting in an accumulation of homocysteine and a concomitant decrease of cystathionine and cysteine in blood and tissues. In mice, the complete lack of CBS is neonatally lethal. In this study, newborn CBS-knockout (KO) mice were treated with recombinant polyethyleneglycolylated human truncated CBS (PEG-CBS). Full survival of the treated KO mice, along with a positive impact on metabolite levels in plasma, liver, brain, and kidneys, was observed. The PEG-CBS treatment prevented an otherwise fatal liver disease characterized by steatosis, death of hepatocytes, and ultrastructural abnormalities of endoplasmic reticulum and mitochondria. Furthermore, treatment of the KO mice for 5 mo maintained the plasma metabolite balance and completely prevented osteoporosis and changes in body composition that characterize both the KO model and human patients. These findings argue that early treatment of patients with HCU with PEG-CBS may prevent clinical symptoms of the disease possibly without the need of dietary protein restriction.-Majtan, T., Hůlková, H., Park, I., Krijt, J., Kožich, V., Bublil, E. M., Kraus, J. P. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria., (© FASEB.)
- Published
- 2017
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32. Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6.
- Author
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Hartmannová H, Piherová L, Tauchmannová K, Kidd K, Acott PD, Crocker JF, Oussedik Y, Mallet M, Hodaňová K, Stránecký V, Přistoupilová A, Barešová V, Jedličková I, Živná M, Sovová J, Hůlková H, Robins V, Vrbacký M, Pecina P, Kaplanová V, Houštěk J, Mráček T, Thibeault Y, Bleyer AJ, and Kmoch S
- Subjects
- Adult, Alleles, Canada, Chromosome Mapping, Exome genetics, Fanconi Syndrome pathology, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Kidney metabolism, Kidney pathology, Lung metabolism, Lung pathology, Male, Middle Aged, Mitochondria pathology, Mitochondrial Diseases metabolism, Mitochondrial Diseases pathology, Mutation, Electron Transport Complex I genetics, Fanconi Syndrome genetics, Mitochondria metabolism, Mitochondrial Diseases genetics, Mitochondrial Proteins genetics
- Abstract
The Acadian variant of Fanconi Syndrome refers to a specific condition characterized by generalized proximal tubular dysfunction from birth, slowly progressive chronic kidney disease and pulmonary interstitial fibrosis. This condition occurs only in Acadians, a founder population in Nova Scotia, Canada. The genetic and molecular basis of this disease is unknown. We carried out whole exome and genome sequencing and found that nine affected individuals were homozygous for the ultra-rare non-coding variant chr8:96046914 T > C; rs575462405, whereas 13 healthy siblings were either heterozygotes or lacked the mutant allele. This variant is located in intron 2 of NDUFAF6 (NM_152416.3; c.298-768 T > C), 37 base pairs upstream from an alternative splicing variant in NDUFAF6 chr8:96046951 A > G; rs74395342 (c.298-731 A > G). NDUFAF6 encodes NADH:ubiquinone oxidoreductase complex assembly factor 6, also known as C8ORF38. We found that rs575462405-either alone or in combination with rs74395342-affects splicing and synthesis of NDUFAF6 isoforms. Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex I deficiency. This information may be used in the diagnosis and prevention of this disease in individuals and families of Acadian descent and broadens the spectrum of the clinical presentation of mitochondrial diseases, respiratory chain defects and defects of complex I specifically., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2016
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33. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
- Author
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Bolar NA, Golzio C, Živná M, Hayot G, Van Hemelrijk C, Schepers D, Vandeweyer G, Hoischen A, Huyghe JR, Raes A, Matthys E, Sys E, Azou M, Gubler MC, Praet M, Van Camp G, McFadden K, Pediaditakis I, Přistoupilová A, Hodaňová K, Vyleťal P, Hartmannová H, Stránecký V, Hůlková H, Barešová V, Jedličková I, Sovová J, Hnízda A, Kidd K, Bleyer AJ, Spong RS, Vande Walle J, Mortier G, Brunner H, Van Laer L, Kmoch S, Katsanis N, and Loeys BL
- Subjects
- Adult, Aged, Alleles, Amino Acid Sequence, Animals, Biopsy, Child, Chronic Disease, Disease Progression, Endoplasmic Reticulum metabolism, Exome genetics, Female, Fetal Growth Retardation genetics, Genes, Dominant, Golgi Apparatus metabolism, Humans, Infant, Newborn, Kidney Diseases pathology, Male, Middle Aged, Models, Molecular, Mutation, Missense genetics, Neutropenia genetics, Pedigree, Phenotype, RNA, Messenger analysis, RNA, Messenger genetics, SEC Translocation Channels chemistry, Syndrome, Young Adult, Zebrafish embryology, Zebrafish genetics, Anemia genetics, Heterozygote, Kidney Diseases genetics, Mutation, SEC Translocation Channels genetics
- Abstract
Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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34. Enzyme replacement with PEGylated cystathionine β-synthase ameliorates homocystinuria in murine model.
- Author
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Bublil EM, Majtan T, Park I, Carrillo RS, Hůlková H, Krijt J, Kožich V, and Kraus JP
- Subjects
- Animals, Cystathionine beta-Synthase genetics, Disease Models, Animal, Homocystinuria pathology, Humans, Liver metabolism, Liver pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Polyethylene Glycols, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins therapeutic use, Cystathionine beta-Synthase deficiency, Cystathionine beta-Synthase therapeutic use, Homocystinuria drug therapy, Homocystinuria metabolism
- Abstract
Homocystinuria, which typically results from cystathionine β-synthase (CBS) deficiency, is the most common defect of sulfur amino acid metabolism. CBS condenses homocysteine and serine to cystathionine that is then converted to cysteine. Individuals with homocystinuria have markedly elevated plasma levels of homocysteine and methionine and reduced concentrations of cystathionine and cysteine. Clinical disease manifestations include thromboembolism and neuropsychiatric, ocular, and skeletal complications. Here, we have shown that administration of PEGylated CBS into the circulation of homocystinuria model mice alters the extra- and intracellular equilibrium of sulfur amino acids, resulting in a decrease of approximately 75% in plasma total homocysteine (tHcy) and normalization of cysteine concentrations. Moreover, the decrease in homocysteine and the normalization of cysteine in PEGylated CBS-treated model mice were accompanied by improvement of histopathological liver symptoms and increased survival. Together, these data suggest that CBS enzyme replacement therapy (ERT) is a promising approach for the treatment of homocystinuria and that ERT for metabolic diseases may not necessitate introduction of the deficient enzyme into its natural intracellular compartment.
- Published
- 2016
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35. Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model.
- Author
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Martins C, Hůlková H, Dridi L, Dormoy-Raclet V, Grigoryeva L, Choi Y, Langford-Smith A, Wilkinson FL, Ohmi K, DiCristo G, Hamel E, Ausseil J, Cheillan D, Moreau A, Svobodová E, Hájková Z, Tesařová M, Hansíková H, Bigger BW, Hrebícek M, and Pshezhetsky AV
- Subjects
- Acetyltransferases deficiency, Acetyltransferases genetics, Animals, Behavior, Animal, Energy Metabolism physiology, Gangliosides metabolism, Glycosaminoglycans metabolism, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins metabolism, Mitochondrial Diseases etiology, Mucopolysaccharidosis III complications, Mucopolysaccharidosis III psychology, Neuritis etiology, Neurodegenerative Diseases etiology, Neurodegenerative Diseases psychology, Neurologic Examination, Proteostasis Deficiencies pathology, Mitochondrial Diseases pathology, Mucopolysaccharidosis III pathology, Neuritis pathology, Neurodegenerative Diseases pathology
- Abstract
Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-β. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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36. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation.
- Author
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Park EJ, Grabińska KA, Guan Z, Stránecký V, Hartmannová H, Hodaňová K, Barešová V, Sovová J, Jozsef L, Ondrušková N, Hansíková H, Honzík T, Zeman J, Hůlková H, Wen R, Kmoch S, and Sessa WC
- Subjects
- Amino Acid Sequence, Animals, Cells, Cultured, Dolichols metabolism, Evolution, Molecular, Female, Gene Knockout Techniques, Glycosylation, Humans, Male, Metabolic Diseases metabolism, Mice, Molecular Sequence Data, Point Mutation, Receptors, Cell Surface chemistry, Receptors, Cell Surface metabolism, Saccharomyces cerevisiae chemistry, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins chemistry, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, Transferases chemistry, Transferases metabolism, Metabolic Diseases genetics, Receptors, Cell Surface genetics, Transferases genetics
- Abstract
Dolichol is an obligate carrier of glycans for N-linked protein glycosylation, O-mannosylation, and GPI anchor biosynthesis. cis-prenyltransferase (cis-PTase) is the first enzyme committed to the synthesis of dolichol. However, the proteins responsible for mammalian cis-PTase activity have not been delineated. Here we show that Nogo-B receptor (NgBR) is a subunit required for dolichol synthesis in yeast, mice, and man. Moreover, we describe a family with a congenital disorder of glycosylation caused by a loss of function mutation in the conserved C terminus of NgBR-R290H and show that fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR. Mutation of NgBR-R290H in man and orthologs in yeast proves the importance of this evolutionarily conserved residue for mammalian cis-PTase activity and function. Thus, these data provide a genetic basis for the essential role of NgBR in dolichol synthesis and protein glycosylation., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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37. Systemic AL amyloidosis with unusual cutaneous presentation unmasked by carotenoderma.
- Author
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Hůlková H, Svojanovský J, Sevela K, Krusová D, Hanuš J, Vězda P, Souček M, Márová I, Feit J, Zambo I, Kovačevicova M, Vlášková H, Kostrouchová V, Novák P, Kostrouch Z, and Elleder M
- Subjects
- Aged, Amyloid metabolism, Amyloidosis blood, Fatal Outcome, Female, Humans, Hyperpigmentation blood, Skin Pigmentation, beta Carotene blood, Amyloidosis diagnosis, Hyperpigmentation diagnosis
- Abstract
We present a case study of an elderly woman with systemic lambda-type AL amyloidosis that featured unusually extensive cutaneous involvement. The case initially presented with a sudden hyper β-carotenemia with carotenoderma that instigated the clinical examination including skin biopsy. A diagnosis of systemic amyloidosis was made. Immunohistochemistry and Western-blot analysis indicated the presence of lambda light chain proteins in skin amyloid deposits. However, notable co-deposition of wild-type apoA-I and transthyretin was observed which caused initial diagnostic confusion. Proteomic analysis of microdissected skin amyloid deposits by mass spectrometry confirmed lambda light chain proteins in amyloid deposits and co-deposition of apolipoprotein A-IV and serum amyloid P-component. The patient died from renal failure caused by amyloid nephropathy combined with analgesic nephropathy. The autopsy disclosed vascular, cardiac, renal and pulmonary amyloid deposition. While all amyloid deposits were positive for lambda light chain proteins, the immunodetection of apoA-I and transthyretin varied significantly among the visceral amyloid deposits. Although the patient exhibited a 1000-fold increase in serum β-carotene levels, only a mild increase in retinol and lutein concentrations was observed. Increased β-carotene values were also found in the liver and the skin. The mechanisms underlying this hyper β-carotenemia remain undetermined.
- Published
- 2014
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38. Mutations in ANTXR1 cause GAPO syndrome.
- Author
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Stránecký V, Hoischen A, Hartmannová H, Zaki MS, Chaudhary A, Zudaire E, Nosková L, Barešová V, Přistoupilová A, Hodaňová K, Sovová J, Hůlková H, Piherová L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martásek P, Baxová A, Afifi HH, St Croix B, Brunner HG, Temtamy S, and Kmoch S
- Subjects
- Alopecia pathology, Alternative Splicing genetics, Anodontia pathology, Base Sequence, Codon, Nonsense genetics, DNA Primers genetics, Extracellular Matrix metabolism, Fibroblasts, Fluorescent Antibody Technique, Gene Frequency, Growth Disorders pathology, Humans, Male, Microfilament Proteins, Molecular Sequence Data, Optic Atrophies, Hereditary pathology, Pedigree, RNA Splice Sites genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Alopecia genetics, Anodontia genetics, Chromosomes, Human, Pair 2 genetics, Extracellular Matrix genetics, Genetic Predisposition to Disease genetics, Growth Disorders genetics, Homeostasis genetics, Neoplasm Proteins genetics, Optic Atrophies, Hereditary genetics, Receptors, Cell Surface genetics
- Abstract
The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435-12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasis., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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39. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing.
- Author
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Kirby A, Gnirke A, Jaffe DB, Barešová V, Pochet N, Blumenstiel B, Ye C, Aird D, Stevens C, Robinson JT, Cabili MN, Gat-Viks I, Kelliher E, Daza R, DeFelice M, Hůlková H, Sovová J, Vylet'al P, Antignac C, Guttman M, Handsaker RE, Perrin D, Steelman S, Sigurdsson S, Scheinman SJ, Sougnez C, Cibulskis K, Parkin M, Green T, Rossin E, Zody MC, Xavier RJ, Pollak MR, Alper SL, Lindblad-Toh K, Gabriel S, Hart PS, Regev A, Nusbaum C, Kmoch S, Bleyer AJ, Lander ES, and Daly MJ
- Subjects
- Cytosine metabolism, Female, Genetic Linkage, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, Male, Mucin-1 metabolism, Minisatellite Repeats genetics, Mucin-1 genetics, Mutation, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
- Published
- 2013
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40. Rapid isolation of lysosomal membranes from cultured cells.
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Mušálková D, Lukáš J, Majer F, Hřebíček O, Svobodová E, Kuchař L, Honzíková J, Hůlková H, Ledvinová J, and Hřebíček M
- Subjects
- Acids metabolism, Adenosine Triphosphate pharmacology, Blotting, Western, Centrifugation, Density Gradient, Glucosylceramidase metabolism, HEK293 Cells, HeLa Cells, Humans, Intracellular Membranes drug effects, Lysosomes drug effects, Subcellular Fractions drug effects, Subcellular Fractions metabolism, Cell Fractionation methods, Intracellular Membranes metabolism, Lysosomes metabolism
- Abstract
We present a simple method for enrichment of lysosomal membranes from HEK293 and HeLa cell lines taking advantage of selective disruption of lysosomes by methionine methyl ester. Organelle concentrate from postnuclear supernatant was treated with 20 mmol/l methionine methyl ester for 45 min to lyse the lysosomes. Subsequently, lysosomal membranes were resolved on a step sucrose gradient. An enriched lysosomal membrane fraction was collected from the 20%/35% sucrose interface. The washed lysosomal membrane fraction was enriched 30 times relative to the homogenate and gave the yield of more than 8%. These results are comparable to lysosomal membranes isolated by magnetic chromatography from cultured cells (Diettrich et al., 1998). The procedure effectively eliminated mitochondrial contamination and minimized contamination from other cell compartments. The enriched fractions retained the ability to acidify membrane vesicles through the activity of lysosomal vacuolar ATPase. The method avoids non-physiological overloading of cells with superparamagnetic particles and appears to be quite robust among the tested cell lines. We expect it may be of more general use, adaptable to other cell lines and tissues.
- Published
- 2013
41. Distinctive histopathological features that support a diagnosis of cholesterol ester storage disease in liver biopsy specimens.
- Author
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Hůlková H and Elleder M
- Subjects
- Cathepsin D metabolism, Child, Child, Preschool, Cholesterol Ester Storage Disease metabolism, Cohort Studies, Diagnosis, Differential, Fatty Liver diagnosis, Fatty Liver metabolism, Fatty Liver pathology, Humans, Infant, Lipid Metabolism, Liver metabolism, Lysosomal-Associated Membrane Protein 2, Lysosomal Membrane Proteins metabolism, Non-alcoholic Fatty Liver Disease, Wolman Disease diagnosis, Wolman Disease metabolism, Wolman Disease pathology, Wolman Disease, Cholesterol Ester Storage Disease diagnosis, Cholesterol Ester Storage Disease pathology, Liver pathology
- Abstract
Aims: To identify reliable criteria with which to improve the diagnosis of lysosomal acid lipase (LAL) deficiency of the cholesterol ester storage disease (CESD) type in liver biopsies., Methods and Results: We analysed a series of 16 liver biopsies of LAL deficiency of the CESD type confirmed by enzyme testing and DNA sequencing. The biopsy appearances were compared with those of biopsies of other causes of fatty liver. A predominantly microvesicular steatosis in CESD patients could not be reliably distinguished from other causes of fatty liver with cytosolic lipid accumulation in fixed paraffin-embedded tissues routinely stained with haematoxylin and eosin. The presence of luminal (cathepsin D) and membrane lysosomal markers [lysosomal-associated membrane protein (LAMP)1, LAMP2, and lysosomal integral membrane protein 2] around the lipid vacuoles facilitated the diagnosis of CESD in fixed paraffin-embedded material. Additional diagnostic clues included autofluorescent detection of ceroid induction in storage macrophages and the absence of lipopigment in hepatocytes. Stored liquid crystals of cholesteryl esters, which are associated with Maltese cross-type birefringence, were best appreciated in unfixed biopsy samples., Conclusions: The pathological diagnosis of CESD requires a high index of suspicion, and can be rapidly and effectively appreciated at the light microscopy level, even in routine fixed paraffin-embedded liver samples with immuohistochemical staining for lysosomal markers., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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42. Glycosphingolipid profile of the apical pole of human placental capillaries: the relevancy of the observed data to Fabry disease.
- Author
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Hůlková H, Ledvinová J, Kuchař L, Šmíd F, Honzíková J, and Elleder M
- Subjects
- Female, Humans, Pregnancy, Tandem Mass Spectrometry, Capillaries metabolism, Fabry Disease metabolism, Glycosphingolipids metabolism, Placenta metabolism
- Abstract
A series of six full-term placentas and umbilical cords were examined using the in situ detection of globotriaosylceramide (Gb3Cer), GM1 ganglioside (GM1), GM3 ganglioside (GM3), cholesterol and caveolin 1. Immunohistochemical study showed uniform distinct staining of the apical membrane of villous capillary endothelial cells for Gb3Cer, GM1, GM3 and cholesterol. There was also a strong signal for caveolin 1. The immunophenotype suggests the presence of caveola-associated raft microdomains. The immunophenotype was almost completely shared with the extravillous intravascular trophoblast in the basal plate. It was absent in the endothelial cells of umbilical vessels and in the capillaries of somatic structures (heart, lung, skeletal muscle and skin) in neonates as well as in adults, including capillaries of the proliferative endometrium. Results of in situ analyses were confirmed by lipid chromatographic analysis of tissue homogenates and by tandem mass spectrometry. Lysosomal Gb3Cer turnover was followed in three placentas including umbilical cords from Fabry disease (α-galactosidase A deficiency). Lysosomal storage was restricted to vascular smooth muscle cells and to endothelial cells of umbilical vessels. Placental villous capillary endothelial cells displaying a strong non-lysosomal staining for Gb3Cer were free of lysosomal storage.
- Published
- 2012
- Full Text
- View/download PDF
43. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.
- Author
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Nosková L, Stránecký V, Hartmannová H, Přistoupilová A, Barešová V, Ivánek R, Hůlková H, Jahnová H, van der Zee J, Staropoli JF, Sims KB, Tyynelä J, Van Broeckhoven C, Nijssen PC, Mole SE, Elleder M, and Kmoch S
- Subjects
- Adult, Age of Onset, Base Sequence, Brain metabolism, Brain pathology, Brain ultrastructure, Chromosome Segregation genetics, Exons genetics, Family, Female, Gene Dosage genetics, Gene Expression Regulation, Genetic Linkage, Humans, Lipoylation, Lysosomes metabolism, Lysosomes ultrastructure, Male, Molecular Sequence Data, Neuronal Ceroid-Lipofuscinoses pathology, Neurons metabolism, Neurons pathology, Neurons ultrastructure, Pedigree, Protein Transport, Sequence Analysis, DNA, Genes, Dominant genetics, HSP40 Heat-Shock Proteins genetics, Membrane Proteins genetics, Mutation genetics, Neuronal Ceroid-Lipofuscinoses epidemiology, Neuronal Ceroid-Lipofuscinoses genetics
- Abstract
Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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44. Adipocytes participate in storage in α-galactosidase deficiency (Fabry disease).
- Author
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Hůlková H and Elleder M
- Subjects
- Adipocytes ultrastructure, Autopsy, Biopsy, Fabry Disease genetics, Fabry Disease pathology, Genetic Predisposition to Disease, Hemizygote, Humans, Lysosomes enzymology, Lysosomes ultrastructure, Male, Mutation, Phenotype, alpha-Galactosidase genetics, Adipocytes enzymology, Fabry Disease enzymology, Glycogen metabolism, alpha-Galactosidase metabolism
- Abstract
Ultrastructural and histochemical studies of bioptic and postmortem tissue samples from ten Fabry hemizygotes showed lysosomal storage in adipocytes as a constant feature of the classic phenotype of α-galactosidase (GLA) deficiency. The storage was represented by a crescent-shaped line of storage lysosomes of varying thicknesses restricted to the perinuclear subplasmalemmal area. The ultrastructure of the storage lysosomes was dominated by concentric lipid membranes modified by simultaneous deposition of autofluorescent ceroid. Storage was widely expressed in adipose tissue. The number of storage lysosomes was increased, and the lysosomes were more clustered in adipocytes with less voluminous lipid content. The findings should attract interest to studies of adipose tissue biology in Fabry disease, a topic that has not been studied so far. In terms of cell biology, the observations represent indirect evidence of significant lysosomal turnover of α-galactose lipid conjugates in adipocytes demasked by GLA deficiency. The results extend the thus far limited information on the adipocyte lysosomal system and its participation in lysosomal storage disorders.
- Published
- 2010
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45. Abnormal nonstoring capillary endothelium: a novel feature of Gaucher disease. Ultrastructural study of dermal capillaries.
- Author
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Hůlková H, Poupetová H, Harzer K, Mistry P, Aerts JM, and Elleder M
- Subjects
- Child, Preschool, Cytoplasm metabolism, Fibroblasts metabolism, Humans, Infant, Lysosomes metabolism, Male, Neovascularization, Pathologic, Pericytes metabolism, Skin pathology, Ultrasonography, Biopsy methods, Capillaries diagnostic imaging, Capillaries pathology, Endothelium, Vascular diagnostic imaging, Endothelium, Vascular pathology, Gaucher Disease diagnostic imaging, Gaucher Disease pathology, Skin blood supply, Skin diagnostic imaging
- Abstract
Ultrastructural study of skin biopsies in two cases of Gaucher disease (GD) patients (types II and III) revealed hitherto unknown alteration of the blood capillary endothelial cells (ECs) featured by hypertrophy and numerous subplasmalemmal microvesicles underneath both the apical and basal membranes. There was also prominent apical membrane folding with formation of filiform and large cytoplasmic projections, with occasional transcapillary cytoplasmic bridges. Similar, though less frequently expressed, changes were manifested at the basal membrane by numerous cytoplasmic projections into the subendothelial space. Regressive changes with EC breakdown were rare. Lysosomal storage was always absent. Besides EC hypertrophy, there was also increased EC density in the capillary lumen, leading to pronounced changes in capillary architecture with loose or incomplete EC anchoring. There were also signs of EC sprouting. Some pericytes displayed an increase in size and number of cytoplasmic processes, which often extended into distant pericapillary regions. The spectrum of changes suggests that a significant positive growth effect on EC occurs in GD. The putative mechanisms triggered by GBA1 deficiency leading to EC involvement are discussed. The authors are well aware of the fact the results, based on a nontraditional type of bioptic samples, are preliminary, but they are worth following, as further ultrastructural and functional studies of blood endothelium in GD may open a novel field in molecular cell pathophysiology of the disorder: endothelial dysfunction.
- Published
- 2010
- Full Text
- View/download PDF
46. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.
- Author
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Zivná M, Hůlková H, Matignon M, Hodanová K, Vylet'al P, Kalbácová M, Baresová V, Sikora J, Blazková H, Zivný J, Ivánek R, Stránecký V, Sovová J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gübler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, and Kmoch S
- Subjects
- Adolescent, Adult, Age of Onset, Anemia metabolism, Cell Line, Child, Child, Preschool, Computer Simulation, Female, Genetic Linkage, Humans, Hyperuricemia metabolism, Kidney cytology, Kidney ultrastructure, Kidney Failure, Chronic metabolism, Male, Middle Aged, Mutation, Pedigree, Renin metabolism, Sequence Analysis, DNA, Young Adult, Anemia genetics, Genes, Dominant, Hyperuricemia genetics, Kidney Failure, Chronic genetics, Renin genetics
- Abstract
Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure.
- Published
- 2009
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47. Subpial astrocytosis and focal leptomeningeal angiotropic astrocytosis leading to vascular compression: observations made in a case of mitochondrial encephalopathy.
- Author
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Hůlková H, Druga R, Ondrejovic P, and Elleder M
- Subjects
- Brain blood supply, Brain metabolism, Cerebrovascular Disorders etiology, Cerebrovascular Disorders pathology, Child, Glial Fibrillary Acidic Protein metabolism, Gliosis complications, Humans, Immunohistochemistry, Male, Meninges blood supply, Meninges metabolism, Mitochondrial Encephalomyopathies metabolism, S100 Proteins metabolism, Brain pathology, Gliosis pathology, Meninges pathology, Mitochondrial Encephalomyopathies pathology
- Published
- 2008
- Full Text
- View/download PDF
48. Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency.
- Author
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Elleder M, Dvoráková L, Stolnaja L, Vlásková H, Hůlková H, Druga R, Poupetová H, Kostálová E, and Mikulástík J
- Subjects
- Adolescent, Age of Onset, Aminopeptidases, Child, Child, Preschool, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Disease Progression, Humans, Inclusion Bodies metabolism, Inclusion Bodies pathology, Male, Mitochondrial Proton-Translocating ATPases metabolism, Neuronal Ceroid-Lipofuscinoses genetics, Neuronal Ceroid-Lipofuscinoses physiopathology, Serine Proteases, Tripeptidyl-Peptidase 1, Brain pathology, Endopeptidases genetics, Neuronal Ceroid-Lipofuscinoses pathology, Neurons pathology
- Abstract
This is the first neuropathology report of a male patient (born 1960-died 1975) with an extremely rare, atypical variant of CLN2 that has been diagnosed only in five families so far. The clinical history started during his preschool years with relatively mild motor and psychological difficulties, but with normal intellect and vision. Since age six there were progressive cerebellar and extrapyramidal symptomatology, amaurosis, and mental deterioration. Epileptic seizures were absent. The child died aged 15 years in extreme cachexy. Neuropathology revealed neurolysosomal storage of autofluorescent, curvilinear and subunit c of mitochondrial ATP synthase (SCMAS) rich material. The neuronal storage led to laminar neuronal depopulation in the cerebral cortex and to a practically total eradication of the cerebellar cortical neurons. The other areas of the central nervous system including hippocampus, which are usually heavily affected in classical forms of CLN2, displayed either a lesser degree or absence of neuronal storage, or storage without significant neuronal loss. Transformation of the stored material to the spheroid like perikaryal inclusions was rudimentary. The follow-up, after 30 years, showed heterozygous values of TPP1 (tripeptidylpeptidase 1) activity in the white blood cells of both parents and the sister. DNA analysis of CLN2 gene identified a paternal frequent null mutation c.622C > T (p.Arg208 X) in the 6th exon and a maternal novel mutation c.1439 T > G in exon 12 (p.Val480Gly). TPP1 immunohistochemistry using a specific antibody gave negative results in the brain and other organs. Our report supports the notion that the spectrum of CLN2 phenotypes may be surprisingly broad. The study revealed variable sensitivities in neuronal subpopulations to the metabolic defect which may be responsible for the variant's serious course.
- Published
- 2008
- Full Text
- View/download PDF
49. Replacement of alpha-galactosidase A in Fabry disease: effect on fibroblast cultures compared with biopsied tissues of treated patients.
- Author
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Keslová-Veselíková J, Hůlková H, Dobrovolný R, Asfaw B, Poupetová H, Berná L, Sikora J, Golán L, Ledvinová J, and Elleder M
- Subjects
- Biopsy, Cells, Cultured, Humans, Male, Microscopy, Confocal, Middle Aged, Myocardium enzymology, alpha-Galactosidase metabolism, Fabry Disease therapy, Fibroblasts enzymology, Genetic Therapy methods, alpha-Galactosidase therapeutic use
- Abstract
The function and intracellular delivery of enzyme therapeutics for Fabry disease were studied in cultured fibroblasts and in the biopsied tissues of two male patients to show diversity of affected cells in response to treatment. In the mutant fibroblasts cultures, the final cellular level of endocytosed recombinant alpha-galactosidases A (agalsidases, Fabrazyme, and Replagal) exceeded, by several fold, the amount in control fibroblasts and led to efficient direct intra-lysosomal hydrolysis of ((3)H)Gb3Cer. In contrast, in the samples from the heart and some other tissues biopsied after several months of enzyme replacement therapy (ERT) with Fabrazyme, only the endothelial cells were free of storage. Persistent Gb3Cer storage was found in cardiocytes (accompanied by increase of lipopigment), smooth muscle cells, fibroblasts, sweat glands, and skeletal muscle. Immunohistochemistry of cardiocytes demonstrated, for the first time, the presence of a considerable amount of the active enzyme in intimate contact with the storage compartment. Factors responsible for the limited ERT effectiveness are discussed, namely post-mitotic status of storage cells preventing their replacement by enzyme supplied precursors, modification of the lysosomal system by longstanding storage, and possible relative lack of Sap B. These observations support the strategy of early treatment for prevention of lysosomal storage.
- Published
- 2008
- Full Text
- View/download PDF
50. Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.
- Author
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Hodanová K, Majewski J, Kublová M, Vyletal P, Kalbácová M, Stibůrková B, Hůlková H, Chagnon YC, Lanouette CM, Marinaki A, Fryns JP, Venkat-Raman G, and Kmoch S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Genetic Linkage, Genotype, Humans, Hyperuricemia metabolism, Kidney metabolism, Male, Middle Aged, Mucoproteins metabolism, Pedigree, Renal Insufficiency, Chronic metabolism, Uromodulin, Chromosome Mapping, Chromosomes, Human, Pair 1, Hyperuricemia genetics, Mucoproteins genetics, Renal Insufficiency, Chronic genetics
- Abstract
Background: Autosomal-dominant juvenile hyperuricemia, gouty arthritis, medullary cysts, and progressive renal insufficiency are features associated with familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2). MCKD1 has been mapped to chromosome 1q21. FJHN and MCKD2 have been mapped to chromosome 16p11.2. FJHN and MCKD2 are allelic, result from uromodulin (UMOD) mutations and the term uromodulin-associated kidney disease (UAKD) has been proposed for them. Linkage studies also reveal families that do not show linkage to any of the identified loci. To identify additional UAKD loci, we analyzed one of these families, with features suggestive of FJHN., Methods: Clinical, biochemical, and immunohistochemical investigations were used for phenotype characterization. Genotyping, linkage and haplotype analyses were employed to identify the candidate disease region. Bioinformatics and sequencing were used for candidate gene selection and analyses., Results: We identified a new candidate UAKD locus on chromosome 1q41, bounded by markers D1S3470 and D1S1644. We analyzed and found no linkage to this region in eight additional families, who did not map to the previously established loci. We noted that affected individuals showed, in addition to the characteristic urate hypoexcretion, significant reductions in urinary excretion of calcium and UMOD. Immunohistochemical analysis showed that low UMOD excretion resulted from its reduced expression, which is a different mechanism to intracellular UMOD accumulation observed in cases with UMOD mutations., Conclusion: We have mapped a new candidate UAKD locus and shown that UAKD may be a consequence of various defects affecting uromodulin biology.
- Published
- 2005
- Full Text
- View/download PDF
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