35 results on '"Suchy SF"'
Search Results
2. Effect of biotin deficiency and supplementation on lipid metabolism in rats: cholesterol and lipoproteins
- Author
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Suchy, SF and Wolf, B
- Published
- 1986
- Full Text
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3. Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans.
- Author
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Bai R, Cui H, Devaney JM, Allis KM, Balog AM, Liu X, Schnur RE, Shapiro FL, Brautbar A, Estrada-Veras JI, Hochstetler L, McConkie-Rosell A, McDonald MT, Solomon BD, Hofherr S, Richard G, and Suchy SF
- Subjects
- Haplotypes, Humans, Male, Phenotype, Retrospective Studies, DNA, Mitochondrial genetics, Mitochondria genetics
- Abstract
Purpose: Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated., Methods: We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study., Results: We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype., Conclusion: These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
- Published
- 2021
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4. SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.
- Author
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Ng BG, Sosicka P, Agadi S, Almannai M, Bacino CA, Barone R, Botto LD, Burton JE, Carlston C, Chung BH, Cohen JS, Coman D, Dipple KM, Dorrani N, Dobyns WB, Elias AF, Epstein L, Gahl WA, Garozzo D, Hammer TB, Haven J, Héron D, Herzog M, Hoganson GE, Hunter JM, Jain M, Juusola J, Lakhani S, Lee H, Lee J, Lewis K, Longo N, Lourenço CM, Mak CCY, McKnight D, Mendelsohn BA, Mignot C, Mirzaa G, Mitchell W, Muhle H, Nelson SF, Olczak M, Palmer CGS, Partikian A, Patterson MC, Pierson TM, Quinonez SC, Regan BM, Ross ME, Guillen Sacoto MJ, Scaglia F, Scheffer IE, Segal D, Singhal NS, Striano P, Sturiale L, Symonds JD, Tang S, Vilain E, Willis M, Wolfe LA, Yang H, Yano S, Powis Z, Suchy SF, Rosenfeld JA, Edmondson AC, Grunewald S, and Freeze HH
- Subjects
- Animals, Biopsy, CHO Cells, Cells, Cultured, Congenital Disorders of Glycosylation metabolism, Congenital Disorders of Glycosylation pathology, Cricetulus, Female, Humans, Male, Mutation, Congenital Disorders of Glycosylation genetics, Monosaccharide Transport Proteins genetics, Monosaccharide Transport Proteins metabolism, Uridine Diphosphate Galactose metabolism
- Abstract
Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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5. De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay.
- Author
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Hiatt SM, Neu MB, Ramaker RC, Hardigan AA, Prokop JW, Hancarova M, Prchalova D, Havlovicova M, Prchal J, Stranecky V, Yim DKC, Powis Z, Keren B, Nava C, Mignot C, Rio M, Revah-Politi A, Hemati P, Stong N, Iglesias AD, Suchy SF, Willaert R, Wentzensen IM, Wheeler PG, Brick L, Kozenko M, Hurst ACE, Wheless JW, Lacassie Y, Myers RM, Barsh GS, Sedlacek Z, and Cooper GM
- Subjects
- Facies, Genotype, Guanosine Diphosphate metabolism, Guanosine Triphosphate metabolism, Humans, Mitochondrial Proteins chemistry, Models, Molecular, Mutation, Missense, Phenotype, Protein Conformation, ral GTP-Binding Proteins chemistry, ras Proteins chemistry, Developmental Disabilities genetics, Intellectual Disability genetics, Mitochondrial Proteins genetics, Mutation, Protein Interaction Domains and Motifs genetics, ral GTP-Binding Proteins genetics, ras Proteins genetics
- Abstract
Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: GMC is currently serving as an Academic Editor for PLOS Genetics. GSB is currently serving as an Editor-In-Chief for PLOS Genetics. ZP is an employee of Ambry Genetics, which provides exome sequencing as a commercially available test. IMW, RW, SFS are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. that also offers commercial exome sequencing. The remaining authors declare no conflicts of interest.
- Published
- 2018
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6. Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation.
- Author
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Ng BG, Xu G, Chandy N, Steyermark J, Shinde DN, Radtke K, Raymond K, Lebrilla CB, AlAsmari A, Suchy SF, Powis Z, Faqeih EA, Berry SA, Kronn DF, and Freeze HH
- Subjects
- Alternative Splicing genetics, Cells, Cultured, Child, Child, Preschool, Fatal Outcome, Female, Fibroblasts metabolism, Fibroblasts pathology, Glycosylation, Humans, Lectins metabolism, Male, Polysaccharides blood, RNA, Messenger genetics, RNA, Messenger metabolism, Alleles, Fucose genetics, Fucosyltransferases genetics, Mutation genetics
- Abstract
Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239
∗ ), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315∗ ). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a congenital disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8-/- knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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7. Familial Exudative Vitreoretinopathy With a Novel LRP5 Mutation.
- Author
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Pefkianaki M, Hasanreisoglu M, Suchy SF, and Shields CL
- Subjects
- Eye Diseases, Hereditary, Familial Exudative Vitreoretinopathies, Fluorescein Angiography, Humans, Infant, Laser Coagulation, Male, Polymerase Chain Reaction, Retinal Detachment diagnosis, Retinal Detachment surgery, Retinal Diseases diagnosis, Low Density Lipoprotein Receptor-Related Protein-5 genetics, Mutation, Retinal Diseases genetics
- Abstract
This report reviews the genetics of familial exudative vitreoretinopathy (FEVR) and describes the identification of a novel variant in the LRP5 gene. A 20-month-old boy presented with reduced visual acuity in the right eye from exudative retinal detachment with mild retinal traction. Fluorescein angiography in the right eye disclosed extensive peripheral retinal non-perfusion and telangiectatic vessels and the left eye showed minimal peripheral non-perfusion. These features were suggestive of FEVR. Treatment with laser photocoagulation and cryotherapy to the region of non-perfusion was performed with resolution of the exudative retinal detachment. Fundus examination of the father revealed mild signs of FEVR, such as hyperacute retinal vascular branching and slight retinal vascular traction, whereas the mother's fundus examination was unremarkable. Genetic testing revealed that the affected boy was negative for mutations in the FZD4, NDP, and TSPAN12 genes and heterozygous for a previously unreported A745V variant in the LRP5 gene. The father was also heterozygous for the A745V variant in the LRP5 gene and the unaffected mother showed no mutation. A genetic evaluation of the known genes associated with FEVR revealed a novel variant in the LRP5 gene that co-segregated with the phenotype in the family. [J Pediatr Ophthalmol Strabismus. 2016;53:e39-e42.]., (Copyright 2016, SLACK Incorporated.)
- Published
- 2016
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8. Corrigendum to "First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children" [Mol. Genet. Metab. Rep. 2 (2016) 81-84].
- Author
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Senanayake DN, Jasinge EA, Pindolia K, Wanigasinghe J, Monaghan K, Suchy SF, Wei S, Jaysena S, and Wolf B
- Abstract
[This corrects the article DOI: 10.1016/j.ymgmr.2015.01.005.].
- Published
- 2016
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9. First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children.
- Author
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Senanayake DN, Jasinge EA, Pindolia K, Wanigasinghe J, Monaghan K, Suchy SF, Wei S, Jaysena S, and Wolf B
- Abstract
We report three symptomatic children with profound biotinidase deficiency from Sri Lanka. All three children presented with typical clinical features of the disorder. The first is homozygous for a missense mutation in the BTD gene (c.98_104 del7insTCC; p.Cys33PhefsX36) that is commonly seen in the western countries, the second is homozygous for a novel missense mutation (p.Ala439Asp), and the third is the first reported instance of a contiguous gene deletion causing the enzyme deficiency. In addition, this latter finding exemplifies the importance of considering a deletion within the BTD gene for reconciling enzymatic activity with genotype, which can occur in asymptomatic children who are identified by newborn screening.
- Published
- 2015
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10. Novel large deletion in the ACTA1 gene in a child with autosomal recessive nemaline myopathy.
- Author
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Friedman B, Simpson K, Tesi-Rocha C, Zhou D, Palmer CA, and Suchy SF
- Subjects
- Child, Preschool, DNA Mutational Analysis, Female, Humans, Muscle, Skeletal pathology, Myopathies, Nemaline pathology, Actins genetics, Myopathies, Nemaline genetics, Sequence Deletion
- Abstract
Nemaline myopathy (NM) is a genetically and clinically heterogeneous disorder resulting from a disruption of the thin filament proteins of the striated muscle sarcomere. The disorder is typically characterized by muscle weakness including the face, neck, respiratory, and limb muscles and is clinically classified based on the age of onset and severity. Mutations in the ACTA1 gene contribute to a significant proportion of NM cases. The majority of ACTA1 gene mutations are missense mutations causing autosomal dominant NM by producing an abnormal protein. However, approximately 10% of ACTA1 gene mutations are associated with autosomal recessive NM; these mutations are associated with loss of protein function. We report the first case of a large deletion in the ACTA1 gene contributing to autosomal recessive NM. This case illustrates the importance of understanding disease mechanisms at the molecular level to accurately infer the inheritance pattern and potentially aid with clinical management., (Copyright © 2014. Published by Elsevier B.V.)
- Published
- 2014
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11. A novel CLCN5 mutation in a boy with asymptomatic proteinuria and focal global glomerulosclerosis.
- Author
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Valina MR, Larsen CP, Kanosky S, Suchy SF, Nield LS, and Onder AM
- Subjects
- Child, Preschool, Glomerulosclerosis, Focal Segmental pathology, Humans, Kidney pathology, Male, Proteinuria pathology, Chloride Channels genetics, Glomerulosclerosis, Focal Segmental genetics, Mutation, Proteinuria genetics
- Abstract
Dent disease is an X-linked proximal tubulopathy that typically presents with hypercalciuria, low-molecular-weight proteinuria and slow progression to endstage renal disease. We report the case of a 5-year-old boy who presented with asymptomatic nephrotic range proteinuria and was later diagnosed with Dent disease. Absence of specific glomerular pathology in the first kidney biopsy led to erroneous treatment for presumably unsampled primary focal segmental glomerulosclerosis. Aggressive angiotensin blockade and immunosuppression resulted in significant side effects with marginal benefit. The continued nonspecific findings after a second kidney biopsy 2 years later led to the suspicion of a congenital tubulopathy. We detected a novel CLCN5 gene mutation, c.1396G > C, that creates a G466R missense change in the ClC-5 protein. Dent disease should be considered in the differential diagnosis of asymptomatic proteinuria for male patients. Profiling proteinuria in these patients by spot urine albumin/creatinine ratio may give the first clue to a tubulopathy. Determining the extent to which the clinical work-up should proceed for females with Dent phenotype or asymptomatic proteinuria remains to be a challenging clinical dilemma.
- Published
- 2013
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12. Abnormal bradykinin signalling in fibroblasts deficient in the PIP(2) 5-phosphatase, ocrl1.
- Author
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Suchy SF, Cronin JC, and Nussbaum RL
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- Blotting, Western, Calcimycin pharmacology, Calcium metabolism, Calcium Signaling genetics, Cell Line, Fibroblasts drug effects, Fibroblasts enzymology, Histamine pharmacology, Humans, Inositol 1,4,5-Trisphosphate Receptors drug effects, Ionophores pharmacology, Phosphoric Monoester Hydrolases genetics, Platelet-Derived Growth Factor pharmacology, Receptors, Bradykinin drug effects, Tubulin metabolism, Bradykinin pharmacology, Calcium Signaling physiology, Fibroblasts physiology, Phosphoric Monoester Hydrolases physiology
- Abstract
The oculocerebrorenal syndrome of Lowe (Lowe syndrome) is an X-linked disorder of phosphatidylinositol metabolism characterized by congenital cataracts, renal proximal tubulopathy and neurological deficits. The disorder is due to the deficiency of the phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase, ocrl1. PIP(2) is critical for numerous cellular processes, including cell signalling, actin reorganization and protein trafficking, and is chronically elevated in patients with Lowe syndrome. The elevation of PIP(2) cells of patients with Lowe syndrome provides the unique opportunity to investigate the roles of this phospholipid in fundamental cellular processes. We previously demonstrated that ocrl1 deficiency causes alterations in the actin cytoskeleton. Since actin remodelling is strongly activated by [Ca(+2)], which increases in response to IP(3) production, we hypothesized that altered calcium signalling might contribute to the observed abnormalities in actin organization. Here we report a specific increase in bradykinin-induced Ca(+2) mobilization in Lowe fibroblasts. We show that the abnormal bradykinin signalling occurs in spite of normal total cellular receptor content. These data point to a novel role for ocrl1 in agonist-induced calcium release.
- Published
- 2009
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13. The effect of missense mutations in the RhoGAP-homology domain on ocrl1 function.
- Author
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Lichter-Konecki U, Farber LW, Cronin JS, Suchy SF, and Nussbaum RL
- Subjects
- Enzyme Activation, Fibroblasts enzymology, GTP Phosphohydrolases analysis, GTPase-Activating Proteins metabolism, Humans, Immunoprecipitation, Mutation, Missense, Oculocerebrorenal Syndrome enzymology, Phosphoric Monoester Hydrolases analysis, Protein Structure, Tertiary, ADP-Ribosylation Factors metabolism, Oculocerebrorenal Syndrome genetics, Phosphoric Monoester Hydrolases genetics, Phosphoric Monoester Hydrolases metabolism
- Abstract
Lowe syndrome is a rare X-linked disease characterized by congenital cataracts, defects in renal tubule cell function, and mental retardation. Mutations in the OCRL1 gene, which encodes ocrl1, a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) 5-phosphatase, are the cause of Lowe syndrome. PtdIns(4,5)P(2), a substrate of ocrl1, is an important signaling molecule within the cell. OCRL1 is ubiquitously expressed and co-localizes with the trans-Golgi network (TGN) and endosomal proteins. The ocrl1 protein contains two recognizable domains, one a conserved Ptd(4,5)P(2) 5-phosphatase domain and the other with homology to Rho GTPase activating proteins (RhoGAPs). The objective of our study was to further characterize the ocrl1 RhoGAP-homology domain by analyzing the effect of two missense mutations in this domain, I751N and A780P, which were previously reported in Lowe syndrome patients. Both mutant proteins were expressed at levels similar to wild-type but their enzyme activity was reduced by 85-90%, indicating that the RhoGAP-homology domain is important for the enzymatic function of ocrl1. Study of a C-terminal region of wild-type ocrl1 containing this domain detected no GAP activity, eliminating the possibility of an effect by mutations in this domain on GTPase activation. Because members of the Arf family of small G-proteins are directly involved in (Ptd(4,5)P(2)) signaling and localize to the TGN like ocrl1, we analyzed by immunoprecipitation the interaction of ocrl1 with Arf1 and Arf6 via its RhoGAP-homology domain. Wild-type ocrl1, but not the I751N mutant protein, co-immunoprecipitated with these two Arf proteins. These results indicate that wild-type ocrl1 and Arf proteins can interact and that this interaction is disrupted by the mutation. It remains unknown whether a disrupted interaction between Arf and ocrl1 plays a role in the Lowe syndrome phenotype.
- Published
- 2006
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14. Dent Disease with mutations in OCRL1.
- Author
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Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, and Scheinman SJ
- Subjects
- Adult, Child, Developmental Disabilities genetics, Fibroblasts, Humans, Intellectual Disability genetics, Male, Oculocerebrorenal Syndrome, Pedigree, Genetic Variation, Kidney Tubules, Proximal physiology, Phosphoric Monoester Hydrolases genetics, Renal Tubular Transport, Inborn Errors genetics
- Abstract
Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported. We studied male probands in 13 families, all of whom met strict criteria for Dent disease but lacked mutations in CLCN5. Linkage analysis in the one large family localized the gene to a candidate region at Xq25-Xq27.1. Sequencing of candidate genes revealed a mutation in the OCRL1 gene. Of the 13 families studied, OCRL1 mutations were found in 5. PIP(2) 5-phosphatase activity was markedly reduced in skin fibroblasts cultured from the probands of these five families, and protein expression, measured by western blotting, was reduced or absent. Slit-lamp examinations performed in childhood or adulthood for all five probands showed normal results. Unlike patients with typical Lowe syndrome, none of these patients had metabolic acidosis. Three of the five probands had mild mental retardation, whereas two had no developmental delay or behavioral disturbance. These findings demonstrate that mutations in OCRL1 can occur with the isolated renal phenotype of Dent disease in patients lacking the cataracts, renal tubular acidosis, and neurological abnormalities that are characteristic of Lowe syndrome. This observation confirms genetic heterogeneity in Dent disease and demonstrates more-extensive phenotypic heterogeneity in Lowe syndrome than was previously appreciated. It establishes that the diagnostic criteria for disorders resulting from mutations in the Lowe syndrome gene OCRL1 need to be revised.
- Published
- 2005
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15. Phosphoinositide profiling in complex lipid mixtures using electrospray ionization mass spectrometry.
- Author
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Wenk MR, Lucast L, Di Paolo G, Romanelli AJ, Suchy SF, Nussbaum RL, Cline GW, Shulman GI, McMurray W, and De Camilli P
- Subjects
- Animals, Brain Chemistry, Cells, Cultured, Feasibility Studies, Mice, Rats, Reproducibility of Results, Sensitivity and Specificity, Cell Extracts chemistry, Lipids analysis, Lipids chemistry, Neurons chemistry, Phosphatidylinositols analysis, Phosphatidylinositols chemistry, Saccharomyces cerevisiae chemistry, Spectrometry, Mass, Electrospray Ionization methods
- Abstract
Phosphoinositides (phosphorylated derivatives of phosphatidylinositol, PI) are versatile intracellular signaling lipids whose occurrence in low concentrations complicates direct mass measurements. Here we present a sensitive method to detect, identify and quantify phosphatidylinositol phosphate (PIP) and phosphatidylinositol bisphosphate (PIP(2)) with different fatty acid compositions (phosphoinositide profiles) in total lipid extracts by electrospray ionization mass spectrometry (ESI-MS). Using this method, we detected elevated concentrations of PIP2 in human fibroblasts from patients with Lowe syndrome, a genetic disorder that affects phosphoinositide metabolism. Saccharomyces cerevisiae cells deficient in enzymes involved in PIP metabolism--Sac1p, a phosphoinositide phosphatase, and Vps34p and Pik1p, a PI 3-kinase and PI 4-kinase, respectively--showed not only different PIP concentrations but also differential changes in PIP profiles indicating metabolic and/or subcellular pooling. Mass spectrometric analysis of phosphoinositides offers unique advantages over existing approaches and may represent a powerful diagnostic tool for human diseases that involve defective phosphoinositide metabolism.
- Published
- 2003
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16. The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization.
- Author
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Suchy SF and Nussbaum RL
- Subjects
- Actinin analysis, Biopolymers chemistry, Biopolymers metabolism, Cytoskeleton enzymology, Fibroblasts, Fluorescent Antibody Technique, Gelsolin analysis, Genotype, Humans, Nerve Tissue Proteins genetics, Oculocerebrorenal Syndrome enzymology, Phenotype, Phosphoric Monoester Hydrolases genetics, Stress Fibers chemistry, Stress Fibers metabolism, Stress Fibers pathology, Actins metabolism, Cytoskeleton metabolism, Cytoskeleton pathology, Nerve Tissue Proteins deficiency, Oculocerebrorenal Syndrome genetics, Oculocerebrorenal Syndrome pathology, Phosphoric Monoester Hydrolases deficiency, Proteins genetics
- Abstract
Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts, renal Fanconi syndrome, and mental retardation. Lowe syndrome results from mutations in the OCRL1 gene, which encodes a phosphatidylinositol 4,5 bisphosphate 5-phosphatase located in the trans-Golgi network. As a first step in identifying the link between ocrl1 deficiency and the clinical disorder, we have identified a reproducible cellular abnormality of the actin cytoskeleton in fibroblasts from patients with Lowe syndrome. The cellular abnormality is characterized by a decrease in long actin stress fibers, enhanced sensitivity to actin depolymerizing agents, and an increase in punctate F-actin staining in a distinctly anomalous distribution in the center of the cell. We also demonstrate an abnormal distribution of two actin-binding proteins, gelsolin and alpha-actinin, proteins regulated by both PIP(2) and Ca(+2) that would be expected to be altered in Lowe cells. Actin polymerization plays a key role in the formation, maintenance, and proper function of tight junctions and adherens junctions, which have been demonstrated to be critical in renal proximal tubule function, and in the differentiation of the lens. These findings point to a general mechanism to explain how this PIP(2) 5-phosphatase deficiency might produce the Lowe syndrome phenotype.
- Published
- 2002
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17. Sertoli cell vacuolization and abnormal germ cell adhesion in mice deficient in an inositol polyphosphate 5-phosphatase.
- Author
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Hellsten E, Bernard DJ, Owens JW, Eckhaus M, Suchy SF, and Nussbaum RL
- Subjects
- Animals, Apoptosis physiology, Cadherins biosynthesis, Cell Adhesion genetics, Cell Membrane physiology, Cytoskeletal Proteins metabolism, Endocytosis physiology, Epithelial Cells physiology, Female, Fertility genetics, Germ Cells ultrastructure, Immunohistochemistry, Inositol Polyphosphate 5-Phosphatases, Intercellular Junctions physiology, Intercellular Junctions ultrastructure, Male, Mice, Mice, Inbred Strains, Microscopy, Electron, Phenotype, Phosphoric Monoester Hydrolases genetics, Testis ultrastructure, Trans-Activators metabolism, beta Catenin, Germ Cells physiology, Phosphoric Monoester Hydrolases deficiency, Sertoli Cells ultrastructure, Vacuoles ultrastructure
- Abstract
The dynamic nature of cellular interactions during differentiation of germ cells and their translocation from the basement membrane to the lumen of the seminiferous tubules requires the existence of complex and well-regulated cellular adhesion mechanisms in the testis. Successful migration of the developing germ cells is characterized by dynamic breakage and reformation of cadherin-containing adherens junctions between the germ cells and Sertoli cells, the polarized somatic cells of the testis that support and nourish the developing gametes. Here, we demonstrate the accumulation of abnormally swollen, actin-coated, endosome-like structures that contain intact adherens junctions and stain positive for N-cadherin and beta-catenin in the Sertoli cell cytosol of mice deficient in Inpp5b, an inositol polyphosphate 5-phosphatase. Simultaneous to the formation of these abnormal structures, developing germ cells are prematurely released from the seminiferous epithelium and sloughed into the epididymis. Our results demonstrate a role for Inpp5b in the regulation of cell adhesion in the testis and in the formation of junctional complexes with neighboring cells, and they emphasize the important and essential role of phosphoinositides in spermatogenesis.
- Published
- 2002
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18. Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells.
- Author
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Dressman MA, Olivos-Glander IM, Nussbaum RL, and Suchy SF
- Subjects
- Adaptor Protein Complex gamma Subunits, Animals, Antibodies, Monoclonal, Antigens, CD metabolism, Cells, Cultured, Chlorocebus aethiops, Fluorescent Antibody Technique, Indirect, Humans, Lysosomal Membrane Proteins, Membrane Glycoproteins metabolism, Membrane Proteins metabolism, Oculocerebrorenal Syndrome metabolism, Proteins immunology, Subcellular Fractions, Vero Cells, Epithelial Cells metabolism, Fibroblasts metabolism, Golgi Apparatus metabolism, Phosphoric Monoester Hydrolases, Proteins metabolism
- Abstract
PtdIns(4,5)P(2) and PtdIns(4,5)P(2) 5-phosphatases play important roles in diverse aspects of cell metabolism, including protein trafficking. However, the relative importance of the PtdIns(4,5)P(2) 5-phosphatases in regulating PtdIns(4,5)P(2) levels for specific cell processes is not well understood. Ocrl1 is a PtdIns(4,5)P(2) 5-phosphatase that is deficient in the oculocerebrorenal syndrome of Lowe, a disorder characterized by defects in kidney and lens epithelial cells and mental retardation. Ocrl1 was originally localized to the Golgi in fibroblasts, but a subsequent report suggested a lysosomal localization in a kidney epithelial cell line. In this study we defined the localization of ocrl1 in fibroblasts and in two kidney epithelial cell lines by three methods: immunofluorescence, subcellular fractionation, and a dynamic perturbation assay with brefeldin A. We found that ocrl1 was a Golgi-localized protein in all three cell types and further identified it as a protein of the trans-Golgi network (TGN). The TGN is a major sorting site and has the specialized function in epithelial cells of directing proteins to the apical or basolateral domains. The epithelial cell phenotype in Lowe syndrome and the localization of ocrl1 to the TGN imply that this PtdIns(4,5)P(2) 5-phosphatase plays a role in trafficking. (J Histochem Cytochem 48:179-189, 2000)
- Published
- 2000
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19. Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease.
- Author
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Mezey E, Dehejia AM, Harta G, Tresser N, Suchy SF, Nussbaum RL, Brownstein MJ, and Polymeropoulos MH
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease genetics, Amino Acid Sequence, DNA Primers, Dementia pathology, Exons, Female, Humans, Male, Middle Aged, Mutation, Missense, Nerve Tissue Proteins immunology, Neurites pathology, Neurons pathology, Peptide Fragments chemistry, Peptide Fragments immunology, Phosphoproteins analysis, Synucleins, alpha-Synuclein, Brain pathology, Lewy Bodies pathology, Nerve Tissue Proteins analysis, Nerve Tissue Proteins genetics, Parkinson Disease genetics, Parkinson Disease pathology, Substantia Nigra pathology
- Abstract
A missense mutation in the human alpha synuclein gene was recently identified in some cases of familial Parkinson's disease (FPD). We have developed an antibody that recognizes the C-terminal 12 amino acids of the human alpha synuclein protein and have demonstrated that alpha synuclein is an abundant component of the Lewy bodies found within the degenerating neurons of patients with Parkinson's disease (PD). The presence of alpha synuclein in Lewy bodies of sporadic PD patients suggests a central role for alpha synuclein in the pathogenesis of PD.
- Published
- 1998
- Full Text
- View/download PDF
20. First report of prenatal biochemical diagnosis of Lowe syndrome.
- Author
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Suchy SF, Lin T, Horwitz JA, O'Brien WE, and Nussbaum RL
- Subjects
- Blotting, Western, Cells, Cultured, Chorionic Villi enzymology, Deoxyribonucleases, Type II Site-Specific metabolism, Female, Fibroblasts enzymology, Humans, Lymphocytes enzymology, Male, Mutation, Phosphoric Monoester Hydrolases genetics, Pregnancy, Amniocentesis, Amniotic Fluid cytology, Oculocerebrorenal Syndrome diagnosis, Phosphoric Monoester Hydrolases analysis
- Abstract
The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder with a severe phenotype characterized by congenital cataracts, renal tubular dysfunction and neurological deficits. The gene has been characterized and mutations have been identified in patients. Owing to the allelic heterogeneity exhibited by this gene, prenatal diagnosis by molecular analysis is limited to families in which the mutation is already known or in which linkage is informative. A more generally applicable diagnostic test would be valuable for families at risk for Lowe syndrome. Since ocrl1 is now known to encode a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ptdlns(4,5)P2 phosphatase), we assessed whether biochemical testing could be used for prenatal diagnosis. We report here the first case of prenatal diagnosis for Lowe syndrome by measuring phosphatidylinositol 4,5-bisphosphate 5-phosphatase activity in cultured amniocytes.
- Published
- 1998
- Full Text
- View/download PDF
21. Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice.
- Author
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Jänne PA, Suchy SF, Bernard D, MacDonald M, Crawley J, Grinberg A, Wynshaw-Boris A, Westphal H, and Nussbaum RL
- Subjects
- Amino Acid Sequence, Amino Acids urine, Animals, Crosses, Genetic, Disease Models, Animal, Gene Expression genetics, Gene Targeting, Humans, Inositol Polyphosphate 5-Phosphatases, Mice, Mice, Knockout, Molecular Sequence Data, Motor Activity physiology, Oculocerebrorenal Syndrome physiopathology, Phenotype, Phosphoric Monoester Hydrolases physiology, Proteins physiology, RNA Splicing, RNA, Messenger metabolism, Stem Cells, Oculocerebrorenal Syndrome genetics, Phosphoric Monoester Hydrolases genetics, Proteins genetics
- Abstract
The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts, and renal tubular dysfunction. The Lowe syndrome gene, OCRL1, encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex. The pathogenesis of Lowe syndrome due to deficiency of a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex is unknown. We have used targeted disruption in embryonic stem cells to make mice deficient in Ocrl1, the mouse homologue for OCRL1, as an animal model for the disease. Surprisingly, mice deficient in Ocrl1 do not develop the congenital cataracts, renal Fanconi syndrome, or neurological abnormalities seen in the human disorder. We hypothesized that Ocrl1 deficiency is complemented in mice by inositol polyphosphate 5-phosphatase (Inpp5b), an autosomal gene that encodes a phosphatidylinositol bisphosphate 5-phosphatase highly homologous to Ocrl1. We created mice deficient in Inpp5b; the mice were viable and fertile without phenotype except for testicular degeneration in males beginning after sexual maturation. We crossed mice deficient in Ocrl1 to mice deficient in Inpp5b. No liveborn mice or embryos lacking both enzymes were found, demonstrating that Ocrl1 and Inpp5b have overlapping functions in mice and suggesting that the lack of phenotype in Ocrl1-deficient mice may be due to compensating Inpp5b function.
- Published
- 1998
- Full Text
- View/download PDF
22. Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients.
- Author
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Lin T, Orrison BM, Suchy SF, Lewis RA, and Nussbaum RL
- Subjects
- Alleles, Alternative Splicing, Cell Line, Codon, Terminator, Exons, Fibroblasts, Frameshift Mutation, Genetic Testing, Humans, Lymphocytes, Male, Point Mutation, Polymorphism, Single-Stranded Conformational, Sequence Analysis, DNA, Sequence Deletion, Mutation, Oculocerebrorenal Syndrome genetics, Phosphoric Monoester Hydrolases genetics, Proteins genetics
- Abstract
Lowe syndrome (OCRL) is an X-linked disorder involving the eyes, kidney, and nervous system that is caused by loss of function in the OCRL1 gene. OCRL1 contains 24 exons (23 of which are coding) and encodes a 105-kDa enzyme with phosphatidylinositol 4,5 bisphosphate (PtdIns[4,5]P2) 5-phosphatase activity. We published previously (1,2) 13 different mutations in 10 families. Four are missense other 8 mutations in 10 families. Four are missense mutations in highly conserved PtdIns (4,5)P2 5-phosphatase caused by nonsense mutations, and three others are premature terminations caused by frameshift mutations. One frameshift, a GT deletion in exon 21, has been observed previously in two unrelated Lowe syndrome patients, suggesting that it may be a relative "hotspot" for mutation in a disorder marked otherwise by allelic heterogeneity. We have also seen two other recurrent mutations. One is a nonsense mutation CGA > TGA in exon 2 observed in two patients and the second is a missense mutation CGA > CAA in exon 15 present in two unrelated patients. These 21 distinct mutations we have found in 25 Lowe syndrome patients occur in only 9 of the 24 exons: 10, 12, 13, 14, 15, 18, 19, 21, and 22. Interestingly, missense mutations have occurred only in exons 12 through 15 in highly conserved residues among the phosphatidylinositol 5-phosphatases. These observations suggest useful strategies for mutation screening in OCRL.
- Published
- 1998
- Full Text
- View/download PDF
23. Disruption of three phosphatidylinositol-polyphosphate 5-phosphatase genes from Saccharomyces cerevisiae results in pleiotropic abnormalities of vacuole morphology, cell shape, and osmohomeostasis.
- Author
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Srinivasan S, Seaman M, Nemoto Y, Daniell L, Suchy SF, Emr S, De Camilli P, and Nussbaum R
- Subjects
- Amino Acid Sequence, Base Sequence, Cell Size, DNA, Fungal, Genes, Fungal, Molecular Sequence Data, Phosphoric Monoester Hydrolases genetics, Saccharomyces cerevisiae cytology, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Vacuoles, Water-Electrolyte Balance, Phosphoric Monoester Hydrolases metabolism, Saccharomyces cerevisiae enzymology, Saccharomyces cerevisiae Proteins
- Abstract
As a result of the genome sequencing project in Saccharomyces cerevisiae, three open reading frames were found in the yeast genome that contain sequences with strong homology to all the domains conserved among the four mammalian phosphatidylinositol-phosphate 5-phosphatases: inpp5bp, ocrl1p, synaptojanin, and ship. In addition, all three yeast gene products shared with synaptojanin regions of homology to the SAC1 gene of yeast. Disruption of each of these genes singly and in pairs produced mutant strains that were viable but demonstrated variable phenotypes of abnormal vacuolar and plasma membrane morphology as well as increased sensitivity to osmotic stress. Total phosphatidylinositol-(4,5)-bisphosphate 5-phosphatase activity was reduced to varying degrees in each of the strains. No defect in carboxypeptidase Y sorting was seen in a processing and targeting assay. Abnormal actin cytoskeleton morphology was present in some of the strains carrying mutations in two of the genes.
- Published
- 1997
24. Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome.
- Author
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Lin T, Orrison BM, Leahey AM, Suchy SF, Bernard DJ, Lewis RA, and Nussbaum RL
- Subjects
- Amino Acid Sequence, Cells, Cultured, Conserved Sequence, Exons, Fibroblasts, Frameshift Mutation, Golgi Apparatus enzymology, Humans, Lymphocytes, Male, Molecular Sequence Data, Phosphoric Monoester Hydrolases chemistry, Point Mutation, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Protein Biosynthesis, Proteins chemistry, Sequence Alignment, Sequence Deletion, Mutation, Oculocerebrorenal Syndrome genetics, Phosphoric Monoester Hydrolases genetics, Proteins genetics
- Abstract
The oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, mental retardation, and renal Fanconi syndrome. The OCRL1 gene, which, when mutated, is responsible for OCRL, encodes a 105-kD Golgi protein with phosphatidylinositol (4,5)bisphosphate (PtdIn[4,5]P2) 5-phosphatase activity. We have examined the OCRL1 gene in 12 independent patients with OCRL and have found 11 different mutations. Six were nonsense mutations, and one a deletion of one or two nucleotides that leads to frameshift and premature termination. In one, a 1.2-kb genomic deletion of exon 14 was identified. In four others, missense mutations or the deletion of a single codon were found to involve amino acid residues known to be highly conserved among proteins with PtdIns(4,5)P2 5-phosphatase activity. All patients had markedly reduced PtdIns(4,5)P2 5-phosphatase activity in their fibroblasts, whereas the ocrl1 protein was detectable by immunoblotting in some patients with either missense mutations or a codon deletion but was not detectable in those with premature termination mutations. These results confirm and extend our previous observation that the OCRL phenotype results from loss of function of the ocrl1 protein and that mutations are generally heterogeneous. Missense mutations that abolish enzyme activity but not expression of the protein will be useful for studying structure-function relationships in PtdIns(4,5)P2 5-phosphatases.
- Published
- 1997
- Full Text
- View/download PDF
25. Lowe syndrome, a deficiency of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi apparatus.
- Author
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Suchy SF, Olivos-Glander IM, and Nussabaum RL
- Subjects
- Cell Line, Cloning, Molecular, Humans, Molecular Sequence Data, Oculocerebrorenal Syndrome genetics, Phosphoric Monoester Hydrolases genetics, Phosphoric Monoester Hydrolases metabolism, Golgi Apparatus enzymology, Oculocerebrorenal Syndrome enzymology, Phosphoric Monoester Hydrolases deficiency, Proteins genetics
- Abstract
The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, renal tubular dysfunction and neurological deficits. The gene responsible for this disorder, OCRL-1, has been cloned and mutations identified in patients. The gene product (ocrl-1) has extensive sequence homology to a 75 kDa inositol polyphosphate 5-phosphatase. We report here that OCRL patients' fibroblasts show no abnormality in inositol polyphosphate 5-phosphatase activity, but are deficient in a phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] 5-phosphatase activity localized to the Golgi apparatus. Direct biochemical diagnosis of this human disease should now be possible. PtdIns(4,5)P2 has been implicated in Golgi vesicular transport through its role in the regulation of ADP-ribosylation factor, phospholipase D and actin assembly in the cytoskeleton. The regulation of PtdIns(4,5)P2 levels by PtdIns(4,5)P2 5-phosphatase may, therefore, be important in the modulation of Golgi vesicular transport. Given that the primary defect in OCRL is a deficiency of a Golgi PtdIns(4,5)P2 phosphatase, we hypothesize that the disorder results from dysregulation of Golgi function and in this way causes developmental defects in the lens and abnormal renal and neurological function.
- Published
- 1995
- Full Text
- View/download PDF
26. The expression of H-like blood group glycolipids in small cell carcinoma of the lung.
- Author
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Cualing H, Siegel R, Schwarting GA, Suchy SF, McCluer RH, and Bernal S
- Subjects
- ABO Blood-Group System immunology, Antibody Specificity, Antigens, Neoplasm immunology, Antigens, Neoplasm isolation & purification, Carcinoma, Small Cell immunology, Cross Reactions, Gangliosides immunology, Glycolipids immunology, Glycolipids isolation & purification, Glycosphingolipids immunology, Humans, Lung Neoplasms immunology, alpha-L-Fucosidase metabolism, Antibodies, Monoclonal immunology, Antibodies, Neoplasm immunology, Antigens, Neoplasm biosynthesis, Carcinoma, Small Cell metabolism, Glycolipids biosynthesis, Lung Neoplasms metabolism
- Abstract
Monoclonal antibody SM1 has been shown to be preferentially reactive with small cell carcinoma of the lung (SCCL) cell lines by fluorescent and radioimmunoassay membrane staining (1). Using solid phase indirect radioimmunoassay, the antigen is not detected in non-SCCL lung carcinomas histologically classified as squamous carcinoma, adenocarcinoma or large cell carcinoma, and other tumors, viz; pheochromocytoma, a mesoderm derived lymphoblastic leukemia cell line or in normal human brain, heart, liver, colon, endothelial tissues of the aorta and blood vessels, skin, omentum, muscle, lung parenchyma and is weakly reactive with bronchial mucosa, pancreas, and kidney. The membrane antigens detected by SM1 were isolated from small cell carcinoma of the lung (SCCL) cell line, SW2, using anion exchange chromatography and thin layer chromatography, and were further analysed by exoglycosidase and endoglycosidase treatments followed by chemical staining and immunostaining with SM1 and other antibodies. We show here that SM1 antibody reacts with a group of fucose-containing neutral glycolipids and gangliosides many of which are cross-reactive with antibodies to H antigens.
- Published
- 1993
- Full Text
- View/download PDF
27. False-positive amniotic fluid acetylcholinesterase analysis in the third trimester.
- Author
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Suchy SF and Yeager MT
- Subjects
- Abdominal Muscles abnormalities, Diagnosis, Differential, Evaluation Studies as Topic, False Positive Reactions, Female, Fetal Growth Retardation diagnosis, Humans, Hydrocephalus diagnosis, Hydrocephalus diagnostic imaging, Neural Tube Defects diagnostic imaging, Polyhydramnios diagnosis, Polyhydramnios diagnostic imaging, Pregnancy, Pregnancy Trimester, Third, Prenatal Diagnosis, Ultrasonography, Acetylcholinesterase analysis, Amniotic Fluid chemistry, Neural Tube Defects diagnosis
- Abstract
Thirty-two third-trimester amniotic fluid samples were studied according to the indication for amniocentesis, result of acetylcholinesterase (AChE) analysis, and outcome, in order to address the issue of the effectiveness of AChE testing late in gestation. The results indicate that third-trimester AChE analysis is less effective than second trimester in distinguishing open neural tube defects (ONTDs) and ventral wall defects (VWDs) from other abnormalities. False-positive results occurred in cases of isolated hydrocephaly (four of seven cases), polyhydramnios, and intrauterine growth retardation (IUGR). Caution is recommended in interpreting third-trimester AChE tests, particularly when neither an ONTD nor a VWD is observed by ultrasound.
- Published
- 1993
- Full Text
- View/download PDF
28. Chondrodysplasia Punctata 1, X-Linked
- Author
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Braverman NE, Bober MB, Brunetti-Pierri N, Suchy SF, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, and Amemiya A
- Abstract
Clinical Characteristics: X-linked chondrodysplasia punctata 1 (CDPX1) is characterized by chondrodysplasia punctata (stippled epiphyses), brachytelephalangy (shortening of the distal phalanges), and nasomaxillary hypoplasia. Although most affected males have minimal morbidity and skeletal findings that improve by adulthood, some have significant medical problems including respiratory involvement, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and intellectual disability., Diagnosis/testing: The diagnosis of CDPX1 is established in a male proband with typical clinical and radiographic findings and a hemizygous ARSL pathogenic variant identified by molecular genetic testing. Testing of ARSL enzymatic activity is not currently available on a clinical basis., Management: Treatment of manifestations: Treatment of respiratory difficulty as per ENT and/or pulmonologist including nasal stents and oxygen as needed. Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals. Instability of the cervical spine may require a cervical collar or spinal fusion. Decompression for cervical spine stenosis as needed. Hearing aids and pressure equalization tubes may be needed for hearing loss. Therapies and individualized education plan for those with developmental delay and/or learning disorder. Standard treatment for vision issues and cardiac anomalies. Surveillance: Routine monitoring for growth deficiency, scoliosis, hearing loss, developmental delay, and ocular abnormalities. Assess for cervical spine instability by flexion-extension radiographs every six to twelve months until growth is completed. Agents/circumstances to avoid: In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided. In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure., Genetic Counseling: CDPX1 is inherited in an X-linked manner. If the mother of a proband has the ARSL pathogenic variant identified in the proband, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and thus far have not been affected. Males with CDPX1 pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for at-risk pregnancies are possible if the ARSL pathogenic variant has been identified in the family., (Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)
- Published
- 1993
29. The expression of a fucosyl-ganglioside in the molecular layer of the dentate gyrus following entorhinal cortical lesions.
- Author
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Suchy SF, Schwarting GA, Lethco BA, and Ramirez JJ
- Subjects
- Animals, Antibodies, Monoclonal, Carbohydrate Conformation, Carbohydrate Sequence, G(M1) Ganglioside analysis, G(M1) Ganglioside biosynthesis, Gangliosides analysis, Gangliosides metabolism, Immunohistochemistry, Male, Molecular Sequence Data, Rats, Rats, Inbred Strains, Reference Values, Synapses physiology, Time Factors, G(M1) Ganglioside analogs & derivatives, Hippocampus physiology
- Abstract
alpha-Galactosyl (alpha-fucosyl) GM1 is a ganglioside present in the outer two-thirds of the molecular layer of the dentate gyrus of the rat. This region is the terminal zone for afferents from the entorhinal cortex. In order to evaluate changes in ganglioside expression in this region following deafferentation, a monoclonal antibody (WCC4) was used to monitor the ganglioside from 3 to 30 days following a lesion to the entorhinal cortex. From 7 to 14 days postlesion, there was a relative decrease in the width of the band of immunohistochemical staining on the ipsilateral (lesioned) as compared with the contralateral (non-lesioned) side. The results of these studies indicate that alpha-galactosyl (alpha-fucosyl) GM1 is likely to be associated with dendritic shafts in the dentate molecular layer.
- Published
- 1991
- Full Text
- View/download PDF
30. Down syndrome screening in women under 35 with maternal serum hCG.
- Author
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Suchy SF and Yeager MT
- Subjects
- Adult, Amniocentesis, Female, Humans, Maternal Age, Mathematical Computing, Pregnancy, Pregnancy Trimester, Second, Risk, Software, Trisomy, alpha-Fetoproteins metabolism, Chorionic Gonadotropin blood, Down Syndrome prevention & control, Mass Screening
- Abstract
Human chorionic gonadotropin and maternal serum alpha-fetoprotein (MSAFP) concentrations were measured in frozen maternal serum samples from 16 pregnancies with Down syndrome and from 614 unaffected pregnancies in women younger than 35. By using only maternal age and MSAFP level to determine Down syndrome risk, four of 16 (25%) Down syndrome pregnancies were identified, using risk estimates as a screening variable. This detection rate required performing amniocentesis on 4.8% of pregnancies with a normal outcome. By adding hCG level as a third risk parameter, ten of 16 (62.5%) Down syndrome pregnancies were detected. To achieve this detection rate, 4.7% of women under 35 would be recommended for amniocentesis. These results indicate that the estimation of risk for Down syndrome based on the addition of maternal hCG level to MSAFP level and maternal age will substantially improve the detection rate for Down syndrome, with no change in the amniocentesis rate. These findings are in agreement with other studies that suggest that hCG is a valuable addition to screening programs for Down syndrome.
- Published
- 1990
31. Amino acids in amniotic fluid in the second trimester of gestation.
- Author
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Mesavage WC, Suchy SF, Weiner DL, Nance CS, Flannery DB, and Wolf B
- Subjects
- Adolescent, Adult, Amino Acids, Branched-Chain analysis, Female, Humans, Pregnancy, Pregnancy Trimester, Second, Reference Values, Amino Acids analysis, Amniotic Fluid analysis
- Abstract
The concentrations of amino acids in amniotic fluid have been used in the prenatal diagnosis of several inherited metabolic disorders. However, previous studies have usually examined only a small number of control amniotic fluid samples. We have, therefore, measured the amino acids in amniotic fluid samples from 183 normal pregnancies between the 13th and the 23rd wk gestation of women ranging in age from 17 to 43 yr. The concentrations of Ala, Lys, Val, Glu, Pro, Thr, and Gly, in descending order, accounted for about 70% of the amino acids in amniotic fluids. A negative correlation with gestational age (-0.34 to -0.24) was found for Leu, Val, Ile, Phe, Lys, Ala, Asp, Tyr, Glu, and Pro, with Leu showing the greatest rate of change. The concentration of Gln increased slightly (r = 0.18), whereas the other amino acids did not change significantly during this period. Statistically significant positive correlations, at all gestational ages, were observed among Val, Leu, and Ile. These branched-chain amino acids also correlated positively with Phe, Lys, Asp, Thr, Ser, Glu, Pro, Gly, Ala, and Tyr, and the amino acids within this group correlated with each other. Additionally, strong positive correlations were observed between Phe and Tyr and between Gly and Ser. No significant correlations were found between any of the amino acids and maternal age or fetal sex. Significant positive correlations between amino acids may be indicative of common transport or degradative pathways and suggest that maintenance of specific relative concentrations in amniotic fluid may be essential for normal fetal development.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1985
- Full Text
- View/download PDF
32. Protein-bound biotin: a consideration in multiple carboxylase deficiency.
- Author
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Suchy SF and Wolf B
- Subjects
- Adult, Age Factors, Blood Proteins metabolism, Carboxy-Lyases metabolism, Humans, Infant, Newborn, Protein Binding, Biotin blood, Carboxy-Lyases deficiency, Metabolism, Inborn Errors blood
- Published
- 1982
- Full Text
- View/download PDF
33. Neurologic symptoms of biotinidase deficiency: possible explanation.
- Author
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Suchy SF, McVoy JS, and Wolf B
- Subjects
- Adolescent, Adult, Aged, Amidohydrolases blood, Amidohydrolases cerebrospinal fluid, Animals, Biotinidase, Brain metabolism, Brain Chemistry, Child, Child, Preschool, Humans, Infant, Middle Aged, Rats, Rats, Inbred Strains, Amidohydrolases deficiency, Nervous System Diseases metabolism
- Abstract
We found that the activity of biotinidase is much lower in human and rat brain or human CSF than in serum or other tissues that have biotin-dependent carboxylase activity. The brain seems to be unable to recycle biotin and depends on biotin transferred across the blood-brain barrier. The biotin-deficient state that results from an inherited lack of biotinidase results in a moderate decrease in brain pyruvate carboxylase activity. This is followed by more severe accumulation of lactate in brain than in other organs, which may explain why affected children have neurologic symptoms before many peripheral features.
- Published
- 1985
- Full Text
- View/download PDF
34. A monoclonal antibody, WCC4, recognizes a developmentally regulated ganglioside containing alpha-galactose and alpha-fucose present in the rat nervous system.
- Author
-
Suchy SF, Yamamoto M, Barbero L, and Schwarting GA
- Subjects
- Adrenal Gland Neoplasms, Aging, Cell Line, Gangliosides immunology, Glycoproteins analysis, Glycoside Hydrolases, Glycosphingolipids isolation & purification, Pheochromocytoma, Antibodies, Monoclonal, Brain growth & development, Fucose analysis, Galactose analysis, Gangliosides analysis
- Abstract
A monoclonal antibody, WCC4, raised against PC12 cells, recognizes a ganglioside which is present in low concentrations in the postnatal rat nervous system. The antigen is also present in the adrenal and kidney, as determined immunohistochemically, but is not detectable in liver or spleen. A neutral glycosphingolipid is also immunoreactive. In the present report, the chemical characterization of this ganglioside, isolated from PC12 cells, and the anatomical distribution of the antigens recognized by the WCC4 antibody are described. By enzymatic cleavage of terminal saccharide moieties, the ganglioside is identified as alpha-galactosyl, (alpha-fucosyl) GM1. The ganglioside increases in concentration postnatally to day 35 (P35) and is present in a slightly diminished concentration in the adult. Immunohistochemical studies revealed that this glycolipid is also present on neuronal cell soma throughout the cerebrum, cerebellum and spinal cord. It is expressed in highest concentration in the molecular layer of the dentate gyrus and is also present in the olfactory bulb, the molecular layer of the hippocampus, the piriform cortex, the olfactory tubercle and the entorhinal cortex. The dentate molecular layer receives most of its innervation from neurons in the entorhinal cortex, and gangliosides are known to have an effect on plasticity following entorhinal cortical lesions. Therefore, the WCC4 antibody should prove to be a useful tool for the study of the role of endogenous gangliosides in this region of the nervous system.
- Published
- 1988
- Full Text
- View/download PDF
35. Glycine/serine ratios in amniotic fluid: an unreliable indicator for the prenatal diagnosis of nonketotic hyperglycinemia.
- Author
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Mesavage C, Nance CS, Flannery DB, Weiner DL, Suchy SF, and Wolf B
- Subjects
- Adolescent, Adult, Amino Acid Metabolism, Inborn Errors genetics, Female, Glycine blood, Humans, Pregnancy, Prenatal Diagnosis, Amino Acid Metabolism, Inborn Errors diagnosis, Amniotic Fluid analysis, Glycine analysis, Serine analysis
- Published
- 1983
- Full Text
- View/download PDF
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