21 results on '"Wolf, Mtf"'
Search Results
2. An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes
- Author
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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
3. Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression
- Author
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Andreas Fischer, Christoph Boehm, Roman S. Polishchuk, Bodo B. Beck, Andreas Pasch, Helmut Hopfer, Massimo Attanasio, Friedhelm Hildebrandt, Matthias T.F. Wolf, Frank Zaucke, Sarah Steffens, Luca Rampoldi, Bernd Hoppe, John A. Sayer, Anne Baasner, Joana M. Boehnlein, Zaucke, F, Boehnlein, Jm, Steffens, S, Polishchuk, R, Rampoldi, L, Fischer, A, Pasch, A, Boehm, Cwa, Baasner, A, Attanasio, M, Hoppe, B, Hopfer, H, Beck, Bb, Sayer, Ja, Hildebrandt, F, and Wolf, Mtf
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Tamm–Horsfall protein ,Biopsy ,030232 urology & nephrology ,Fluorescent Antibody Technique ,Kinesins ,Kidney ,Mice ,0302 clinical medicine ,Mucoproteins ,Child ,Genetics (clinical) ,Cells, Cultured ,Cystic kidney ,0303 health sciences ,medicine.diagnostic_test ,Cilium ,General Medicine ,Articles ,Middle Aged ,3. Good health ,Protein Transport ,medicine.anatomical_structure ,Renal biopsy ,Cell Division ,Adult ,medicine.medical_specialty ,Adolescent ,Blotting, Western ,Biology ,Transfection ,Antibodies ,03 medical and health sciences ,Cystic kidney disease ,Young Adult ,Internal medicine ,Uromodulin ,Genetics ,medicine ,Animals ,Humans ,Cilia ,Molecular Biology ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Kidney metabolism ,Membrane Proteins ,medicine.disease ,Cytoskeletal Proteins ,Endocrinology ,Membrane protein ,Mutation ,biology.protein ,Mutant Proteins - Abstract
Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the 'nephronophthisis-MCKD complex', a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney disease.
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- 2010
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4. Nephronophthisis: a pathological and genetic perspective.
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Wolf MTF, Bonsib SM, Larsen CP, and Hildebrandt F
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- Humans, Ciliopathies genetics, Ciliopathies pathology, Cilia pathology, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic pathology
- Abstract
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents. Over 20 genes cause NPHP and over 90 genes contribute to renal ciliopathies often involving multiple organs. About 15-20% of NPHP patients have additional extrarenal symptoms affecting other organs than the kidneys. The involvement of additional organ systems in syndromic forms of NPHP is explained by shared expression of most NPHP gene products in centrosomes and primary cilia, a sensory organelle present in most mammalian cells. This finding resulted in the classification of NPHP as a ciliopathy. If extrarenal symptoms are present in addition to NPHP, these disorders are defined as NPHP-related ciliopathies (NPHP-RC) and can involve the retina (e.g., with Senior-Løken syndrome), CNS (central nervous system) (e.g., with Joubert syndrome), liver (e.g., Boichis and Arima syndromes), or bone (e.g., Mainzer-Saldino and Sensenbrenner syndromes). This review focuses on the pathological findings and the recent genetic advances in NPHP and NPHP-RC. Different mechanisms and signaling pathways are involved in NPHP ranging from planar cell polarity, sonic hedgehog signaling (Shh), DNA damage response pathway, Hippo, mTOR, and cAMP signaling. A number of therapeutic interventions appear to be promising, ranging from vasopressin receptor 2 antagonists such as tolvaptan, cyclin-dependent kinase inhibitors such as roscovitine, Hh agonists such as purmorphamine, and mTOR inhibitors such as rapamycin., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)
- Published
- 2024
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5. Ghrelin enhances tubular magnesium absorption in the kidney.
- Author
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Nie M, Zhang J, Bal M, Duran C, An SW, Zigman JM, Baum M, Hiremath C, Marciano DK, and Wolf MTF
- Abstract
Osteoporosis after bariatric surgery is an increasing health concern as the rate of bariatric surgery has risen. In animal studies mimicking bariatric procedures, bone disease, together with decreased serum levels of Ca
2+ , Mg2+ and the gastric hormone Ghrelin were described. Ghrelin regulates metabolism by binding to and activating the growth hormone secretagogue receptor (GHSR) which is also expressed in the kidney. As calcium and magnesium are key components of bone, we tested the hypothesis that Ghrelin-deficiency contributes to osteoporosis via reduced upregulation of the renal calcium channel TRPV5 and the heteromeric magnesium channel TRPM6/7. We expressed GHSR with TRPV5 or TRPM6/7 channel in HEK293 cells and treated them with purified Ghrelin. Whole-cell current density was analyzed by patch-clamp recording. Nephron-specific gene expression was performed by tubular microdissection followed by qPCR in wild-type (WT) mice, and immunofluorescent imaging of GHSR-eGFP mice. Tubular magnesium homeostasis was analyzed in GHSR-null and WT mice at baseline and after caloric restriction. After Ghrelin exposure, whole-cell current density did not change for TRPV5 but increased for TRPM6/7 in a dose-dependent fashion. Applying the Ghrelin-mimetic (D-Trp7 , Ala8 ,D-Phe10 )-α-MSH (6-11) amide without and with the GHSR antagonist (D-Lys3 )-GHRP6, we confirmed the stimulatory role of Ghrelin towards TRPM6/7. As GHSR initiates downstream signaling via protein kinase A (PKA), we found that the PKA inhibitor H89 abrogated TRPM6/7 stimulation by Ghrelin. Similarly, transfected Gαs , but not the Gαs mutant Q227L, nor Gαi2 , Gαq , or Gα13 upregulated TRPM6/7 current density. In microdissected TALs and DCTs similar levels of GHSR mRNA were detected. In contrast, TRPM6 mRNA was expressed in the DCT and also detected in the TAL at 25% expression compared to DCT. Immunofluorescent studies using reporter GHSR-eGFP mice showed a strong eGFP signal in the TAL but surprisingly displayed no eGFP signal in the DCT. In 3-, 6-, and 9-month-old GHSR-null and WT mice, baseline serum magnesium was not significantly different, but 24-h urinary magnesium excretion was elevated in 9-month-old GHSR-null mice. In calorically restricted GHSR-null mice, we detected excess urinary magnesium excretion and reduced serum magnesium levels compared to WT mice. The kidneys from calorically restricted WT mice showed upregulated gene expression of magnesiotropic genes Hnf1b , Cldn-16 , Cldn-19 , Fxyd-2b , and Parvalbumin compared to GHSR-null mice. Our in vitro studies show that Ghrelin stimulates TRPM6/7 via GHSR and Gαs -PKA signaling. The murine studies are consistent with Ghrelin-GHSR signaling inducing reduced urinary magnesium excretion, particularly in calorically restricted mice when Ghrelin levels are elevated. This effect may be mediated by Ghrelin-upregulation of TRPM6 in the TAL and/or upregulation of other magnesiotropic genes. We postulate that rising Ghrelin levels with hunger contribute to increased renal Mg2+ reabsorption to compensate for lack of enteral Mg2+ uptake., Competing Interests: JMZ owns stock in Eli Lilly, Novo Nordisk, and Medtronic. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nie, Zhang, Bal, Duran, An, Zigman, Baum, Hiremath, Marciano and Wolf.)- Published
- 2024
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6. Early therapy with sirolimus reduces size of a large solid renal mass but not seizure activity in an infant with tuberous sclerosis.
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Hani SB, Artunduaga M, Ludwig K, Bissler JJ, and Wolf MTF
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- Infant, Humans, Secondary Prevention, Immunosuppressive Agents adverse effects, Kidney, Sirolimus therapeutic use, Tuberous Sclerosis complications, Tuberous Sclerosis drug therapy
- Published
- 2024
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7. Physiology of a Forgotten Electrolyte-Magnesium Disorders.
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Ray E, Mohan K, Ahmad S, and Wolf MTF
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- Humans, Female, Magnesium, Electrolytes, Homeostasis, Memory Disorders, Diabetes Mellitus, Type 2, Water-Electrolyte Imbalance
- Abstract
Magnesium (Mg
2+ ) is the second most common intracellular cation and the fourth most abundant element on earth. However, Mg2+ is a frequently overlooked electrolyte and often not measured in patients. While hypomagnesemia is common in 15% of the general population, hypermagnesemia is typically only found in preeclamptic women after Mg2+ therapy and in patients with ESRD. Mild to moderate hypomagnesemia has been associated with hypertension, metabolic syndrome, type 2 diabetes mellitus, CKD, and cancer. Nutritional Mg2+ intake and enteral Mg2+ absorption are important for Mg2+ homeostasis, but the kidneys are the key regulators of Mg2+ homeostasis by limiting urinary excretion to less than 4% while the gastrointestinal tract loses over 50% of the Mg2+ intake in the feces. Here, we review the physiological relevance of Mg2+ , the current knowledge of Mg2+ absorption in the kidneys and the gut, the different causes of hypomagnesemia, and a diagnostic approach on how to assess Mg2+ status. We highlight the latest discoveries of monogenetic conditions causing hypomagnesemia, which have enhanced our understanding of tubular Mg2+ absorption. We will also discuss external and iatrogenic causes of hypomagnesemia and advances in the treatment of hypomagnesemia., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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8. The roles of homocysteinemia and methylmalonic acidemia in kidney injury in atypical hemolytic uremic syndrome caused by cobalamin C deficiency.
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Wood WD, Elmaghrabi A, Gotway G, and Wolf MTF
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- Amino Acid Metabolism, Inborn Errors, Female, Homocysteine, Humans, Infant, Newborn, Kidney pathology, Methylmalonic Acid, Oxidoreductases genetics, Vitamin B 12, Acute Kidney Injury etiology, Atypical Hemolytic Uremic Syndrome complications, Atypical Hemolytic Uremic Syndrome diagnosis, Atypical Hemolytic Uremic Syndrome genetics, Hyperhomocysteinemia complications, Thrombotic Microangiopathies pathology, Vitamin B 12 Deficiency complications, Vitamin B 12 Deficiency diagnosis
- Abstract
Background: Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA. CblC deficiency, an inborn error of cobalamin processing, is a rare cause of atypical hemolytic-uremic syndrome (aHUS) and results in hyperhomocysteinemia and methylmalonic aciduria. Both substances are thought to contribute to thrombotic microangiopathy (TMA) in cblC deficiency patients. However, the roles of homocysteine and methylmalonic acid (MMA) in these patients remain unclear. We want to shed more light on the contributions of homocysteine and MMA levels as contributing factors for thrombotic microangiopathy (TMA)/aHUS by a follow-up of a cblC deficiency patient over 6 years., Case Diagnosis: A 27-day-old Hispanic female presented with abnormal C3-carnitine on her newborn screen, poor feeding, decreased activity, and oligouria. She was diagnosed with cblC deficiency after laboratory results revealed elevated serum homocysteine, and serum MMA along with genetic testing showing a homozygous pathogenic frameshift variant in MMACHC. The patient developed aHUS and acute kidney injury (AKI), which resolved after appropriate therapy. Over 6 years, she continued to have normal kidney function with no thrombocytopenia despite persistently elevated homocysteine and MMA levels., Conclusion: We question the roles of homocysteine and MMA as causative of aHUS/TMA in cblC deficiency as they remained elevated during follow-up but did not result in aHUS/TMA or AKI. Hyperhomocysteinemia and/or MMA caused by other metabolic diseases do not result in aHUS/TMA or AKI. This suggests that other nephrotoxic factors may trigger aHUS/TMA in cblC patients., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)
- Published
- 2022
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9. A narrative review of Hyporeninemic hypertension-an indicator for monogenic forms of hypertension.
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Mashmoushi A and Wolf MTF
- Abstract
Background and Objective: While the role of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertension is well known, the significance and contribution of low renin hypertension is often overlooked. RAAS stimulation results in more tubular absorption of sodium and water along the nephron, contributing to a higher circulating vascular volume. In addition, members of the RAAS system, such as angiotensin II, have direct effects on vascular vasoconstriction, the heart, aldosterone synthesis in the adrenal glands, the sympathetic nervous system, and the central nervous system. This has resulted in a line of antihypertensive therapeutics targeting RAAS with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors, which prevent conversion of angiotensinogen to angiotensin. While general practitioners and nephrologists are well aware of the causes and the long-term consequences of elevated renin and aldosterone levels, the opposite situation with low renin and/or low aldosterone levels is frequently underappreciated. The objective of this review is to provide insight to the less common forms of hyporeninemic hypertension., Methods: We searched the PubMed online library for keywords related to hyporeninemic hypertension and focused on the pediatric population. For pathophysiology we focused on literature of the last 5 years., Key Content and Findings: The low renin and aldosterone levels may be indicators of inherited (especially when associated with hypokalemia), monogenic forms of hypertension stimulating excessive tubular sodium and water absorption which subsequently results in plasma volume expansion and hypertension. These forms of hypertension require frequently specific forms of therapy. This underlines the importance of the practitioner to be familiar with these rare diseases., Conclusions: In this review article, we outline the different forms of hypertension characterized by low renin/low aldosterone and low renin/high aldosterone levels, how to diagnose these forms of hypertension, and how to treat them., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-21-48/coif). Dr. MTFW reports research funding from the Department of Defense (W81XWH1910205), the National Institute of Health (P30 DK079328–11, R01DK119631), and the Children’s Clinical Research Advisory Committee (CCRAC). The other author has no conflicts of interest to declare.
- Published
- 2022
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10. A rare case of hyporeninemic hypertension: Answers.
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Mashmoushi A, Choudhary A, Thomas CP, and Wolf MTF
- Published
- 2021
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11. A rare case of hyporeninemic hypertension: Questions.
- Author
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Mashmoushi A, Choudhary A, Thomas CP, and Wolf MTF
- Published
- 2021
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12. 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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13. Homozygous NEK8 Mutations in Siblings With Neonatal Cholestasis Progressing to End-stage Liver, Renal, and Cardiac Disease.
- Author
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Hassan S, Wolf MTF, Umaña LA, Malik S, Uddin N, Andersen J, and Aqul A
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- Child, Preschool, Fatal Outcome, Female, Homozygote, Humans, Infant, Infant, Newborn, Male, Mutation, Pedigree, Siblings, Cholestasis genetics, End Stage Liver Disease genetics, Heart Diseases genetics, Kidney Failure, Chronic genetics, NIMA-Related Kinases genetics
- Published
- 2020
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14. Phosphorylated claudin-16 interacts with Trpv5 and regulates transcellular calcium transport in the kidney.
- Author
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Hou J, Renigunta V, Nie M, Sunq A, Himmerkus N, Quintanova C, Bleich M, Renigunta A, and Wolf MTF
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- Animals, Calcium Channels genetics, Cell Membrane Permeability, Claudins antagonists & inhibitors, Claudins genetics, HEK293 Cells, Humans, Male, Mice, Mice, Knockout, Phosphorylation, TRPV Cation Channels antagonists & inhibitors, TRPV Cation Channels genetics, Calcium metabolism, Calcium Channels metabolism, Claudins metabolism, Kidney Tubules, Distal metabolism, TRPV Cation Channels metabolism, Tight Junctions metabolism, Transcytosis
- Abstract
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was previously considered to be a paracellular channelopathy caused by mutations in the claudin-16 and claudin-19 genes. Here, we provide evidence that a missense FHHNC mutation c.908C>G (p.T303R) in the claudin-16 gene interferes with the phosphorylation in the claudin-16 protein. The claudin-16 protein carrying phosphorylation at residue T303 is localized in the distal convoluted tubule (DCT) but not in the thick ascending limb (TAL) of the mouse kidney. The phosphomimetic claudin-16 protein carrying the T303E mutation but not the wildtype claudin-16 or the T303R mutant protein increases the Trpv5 channel conductance and membrane abundance in human kidney cells. Phosphorylated claudin-16 and Trpv5 are colocalized in the luminal membrane of the mouse DCT tubule; phosphomimetic claudin-16 and Trpv5 interact in the yeast and mammalian cell membranes. Knockdown of claudin-16 gene expression in transgenic mouse kidney delocalizes Trpv5 from the luminal membrane in the DCT. Unlike wildtype claudin-16, phosphomimetic claudin-16 is delocalized from the tight junction but relocated to the apical membrane in renal epithelial cells because of diminished binding affinity to ZO-1. High-Ca
2+ diet reduces the phosphorylation of claudin-16 protein at T303 in the DCT of mouse kidney via the PTH signaling cascade. Knockout of the PTH receptor, PTH1R, from the mouse kidney abrogates the claudin-16 phosphorylation at T303. Together, these results suggest a pathogenic mechanism for FHHNC involving transcellular Ca2+ pathway in the DCT and identify a molecular component in renal Ca2+ homeostasis under direct regulation of PTH., Competing Interests: The authors declare no conflict of interest.- Published
- 2019
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15. Uromodulin in mineral metabolism.
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Wolf MTF, Zhang J, and Nie M
- Subjects
- Animals, Calcium metabolism, Humans, Hypertension etiology, Hypertension metabolism, Ion Transport, Kidney Tubules metabolism, Magnesium metabolism, Renal Insufficiency, Chronic etiology, Uromodulin blood, Minerals metabolism, Uromodulin physiology
- Abstract
Purpose of Review: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is the most abundant protein in human urine. UMOD has multiple functions such as protection against urinary tract infections and nephrolithiasis. This review outlines recent progress made in UMOD's role in renal physiology, tubular transport, and mineral metabolism., Recent Findings: UMOD is mostly secreted in the thick ascending limb (TAL) and to a lesser degree in the distal convoluted tubule (DCT). UMOD secretion is regulated by the calcium-sensing receptor. UMOD upregulates ion channels [e.g., renal outer medullary potassium channel, transient receptor potential cation channel subfamily V member 5, and transient receptor potential melastatin 6 (TRPM6)] and cotransporters [e.g., Na,K,2Cl cotransporter (NKCC2) and sodium-chloride cotransporter (NCC)] in the TAL and DCT. Higher serum UMOD concentrations have been associated with higher renal function and preserved renal reserve. Higher serum UMOD has also been linked to a lower risk of cardiovascular disease and diabetes mellitus., Summary: With better serum UMOD detection assays the extent of different functions for UMOD is still expanding. Urinary UMOD regulates different tubular ion channels and cotransporters. Variations of urinary UMOD secretion can so contribute to common disorders such as hypertension or nephrolithiasis.
- Published
- 2019
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16. Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6).
- Author
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Nie M, Bal MS, Liu J, Yang Z, Rivera C, Wu XR, Hoenderop JGJ, Bindels RJM, Marciano DK, and Wolf MTF
- Subjects
- Animals, Endocytosis, Furosemide pharmacology, Humans, Kidney Tubules, Distal metabolism, Magnesium urine, Mice, Mice, Knockout, Uromodulin genetics, Homeostasis, Kidney chemistry, Magnesium metabolism, TRPM Cation Channels metabolism, Uromodulin physiology
- Abstract
Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod -knockout ( Umod
-/- ) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod-/- mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod-/- mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamin-dependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses., (© 2018 Nie et al.)- Published
- 2018
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17. Mercury Intoxication as a Rare Cause of Membranous Nephropathy in a Child.
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Onwuzuligbo O, Hendricks AR, Hassler J, Domanski K, Goto C, and Wolf MTF
- Subjects
- Adolescent, Biopsy, Needle, Disease Progression, Follow-Up Studies, Glomerulonephritis, Membranous pathology, Humans, Immunohistochemistry, Male, Mercury Poisoning complications, Nephrotic Syndrome diagnostic imaging, Nephrotic Syndrome therapy, Rare Diseases, Risk Assessment, Environmental Exposure adverse effects, Glomerulonephritis, Membranous chemically induced, Glomerulonephritis, Membranous therapy, Mercury adverse effects, Nephrotic Syndrome pathology
- Abstract
In adults, membranous nephropathy is the second most common cause of nephrotic syndrome. In contrast, minimal change disease and focal segmental glomerulosclerosis constitute the most common forms of nephrotic syndrome in children, while membranous nephropathy accounts for <5% of cases. In adults, causes of membranous nephropathy include autoantibodies directed against phospholipase A
2 receptor and thrombospondin type 1 containing 7A, various infections, environmental toxicities, autoimmune disorders, malignancies, and other secondary forms. The most common causes of secondary membranous nephropathy in children are infections, autoimmune diseases, and neoplasia. We discuss an unusual presentation of new-onset membranous nephropathy due to mercury toxicity in a 14-year-old male with reflux nephropathy. This case underscores the importance of a high index of suspicion for uncommon causes of nephrotic syndrome in pediatric patients with membranous nephropathy., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
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18. Single molecule real time sequencing in ADTKD-MUC1 allows complete assembly of the VNTR and exact positioning of causative mutations.
- Author
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Wenzel A, Altmueller J, Ekici AB, Popp B, Stueber K, Thiele H, Pannes A, Staubach S, Salido E, Nuernberg P, Reinhardt R, Reis A, Rump P, Hanisch FG, Wolf MTF, Wiesener M, Huettel B, and Beck BB
- Subjects
- Cohort Studies, DNA Mutational Analysis, Female, Humans, Male, Alleles, High-Throughput Nucleotide Sequencing, Minisatellite Repeats, Mucin-1 genetics, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubulointerstitial kidney disease (ADTKD). Most causative mutations are buried within a GC-rich 60 basepair variable number of tandem repeat (VNTR), which escapes identification by massive parallel sequencing methods due to the complexity of the VNTR. We established long read single molecule real time sequencing (SMRT) targeted to the MUC1-VNTR as an alternative strategy to the snapshot assay. Our approach allows complete VNTR assembly, thereby enabling the detection of all variants residing within the VNTR and simultaneous determination of VNTR length. We present high resolution data on the VNTR architecture for a cohort of snapshot positive (n = 9) and negative (n = 7) ADTKD families. By SMRT sequencing we could confirm the diagnosis in all previously tested cases, reconstruct both VNTR alleles and determine the exact position of the causative variant in eight of nine families. This study demonstrates that precise positioning of the causative mutation(s) and identification of other coding and noncoding sequence variants in ADTKD-MUC1 is feasible. SMRT sequencing could provide a powerful tool to uncover potential factors encoded within the VNTR that associate with intra- and interfamilial phenotype variability of MUC1 related kidney disease.
- Published
- 2018
- Full Text
- View/download PDF
19. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.
- Author
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Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, Gribouval O, Boyer O, Revy P, Jobst-Schwan T, Schmidt JM, Lawson JA, Schanze D, Ashraf S, Ullmann JFP, Hoogstraten CA, Boddaert N, Collinet B, Martin G, Liger D, Lovric S, Furlano M, Guerrera IC, Sanchez-Ferras O, Hu JF, Boschat AC, Sanquer S, Menten B, Vergult S, De Rocker N, Airik M, Hermle T, Shril S, Widmeier E, Gee HY, Choi WI, Sadowski CE, Pabst WL, Warejko JK, Daga A, Basta T, Matejas V, Scharmann K, Kienast SD, Behnam B, Beeson B, Begtrup A, Bruce M, Ch'ng GS, Lin SP, Chang JH, Chen CH, Cho MT, Gaffney PM, Gipson PE, Hsu CH, Kari JA, Ke YY, Kiraly-Borri C, Lai WM, Lemyre E, Littlejohn RO, Masri A, Moghtaderi M, Nakamura K, Ozaltin F, Praet M, Prasad C, Prytula A, Roeder ER, Rump P, Schnur RE, Shiihara T, Sinha MD, Soliman NA, Soulami K, Sweetser DA, Tsai WH, Tsai JD, Topaloglu R, Vester U, Viskochil DH, Vatanavicharn N, Waxler JL, Wierenga KJ, Wolf MTF, Wong SN, Leidel SA, Truglio G, Dedon PC, Poduri A, Mane S, Lifton RP, Bouchard M, Kannu P, Chitayat D, Magen D, Callewaert B, van Tilbeurgh H, Zenker M, Antignac C, and Hildebrandt F
- Subjects
- Animals, Apoptosis genetics, CRISPR-Cas Systems, Carrier Proteins genetics, Cell Movement, Cytoskeleton ultrastructure, DNA Repair genetics, Endoplasmic Reticulum Stress genetics, Gene Knockout Techniques, Humans, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Metalloendopeptidases deficiency, Metalloendopeptidases genetics, Mice, Models, Molecular, Nephrotic Syndrome genetics, Nephrotic Syndrome pathology, Podocytes metabolism, Podocytes ultrastructure, Protein Conformation, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, RNA Processing, Post-Transcriptional genetics, RNA, Transfer metabolism, Telomere Homeostasis genetics, Zebrafish, Zebrafish Proteins deficiency, Zebrafish Proteins genetics, Hernia, Hiatal genetics, Microcephaly genetics, Multiprotein Complexes genetics, Mutation, Nephrosis genetics
- Abstract
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
- Published
- 2017
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20. Omental Arteriopathy in Primary Atypical Hemolytic Uremic Syndrome.
- Author
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Ellington N, Wolf MTF, Kasten J, and Rakheja D
- Subjects
- Atypical Hemolytic Uremic Syndrome diagnosis, Atypical Hemolytic Uremic Syndrome genetics, Circumcision, Male adverse effects, Complement Factor B genetics, Genetic Testing, Humans, Infant, Newborn, Male, Multiple Organ Failure etiology, Multiple Organ Failure therapy, Omentum surgery, Peritoneal Dialysis, Photomicrography, Postoperative Hemorrhage etiology, Vascular Diseases etiology, Vascular Diseases surgery, Arteries pathology, Atypical Hemolytic Uremic Syndrome complications, Omentum blood supply, Vascular Diseases pathology
- Published
- 2017
- Full Text
- View/download PDF
21. Pulmonary re-occurrence of post-transplant lymphoproliferative disease with hypogammaglobulinaemia.
- Author
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Wolf MTF, Mildenberger E, Lennert T, Anagnostopoulos I, Zinn C, Paul K, Keitzer R, and Versmold H
- Subjects
- Agammaglobulinemia virology, Cell Transformation, Neoplastic, Child, Epstein-Barr Virus Infections complications, Humans, Lymphoma, B-Cell virology, Lymphoproliferative Disorders virology, Male, Pneumonia etiology, Recurrence, Agammaglobulinemia etiology, Epstein-Barr Virus Infections etiology, Kidney Transplantation adverse effects, Lymphoma, B-Cell etiology, Lymphoproliferative Disorders etiology
- Abstract
Unlabelled: We report the case of a 12-year-old boy, who developed Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) 7 years after renal transplantation. He responded well to the reduced immunosuppressive therapy and treatment with ganciclovir. Two years later he developed severe pneumonia and hypogammaglobulinaemia related to EBV infection exacerbation. An X-ray film revealed persistent pneumonia in the right lung. Lung biopsy showed a large, diffuse EBV-associated B-cell lymphoma. This constellation suggested re-occurrence of the primary PTLD., Conclusion: We present a case of recurring Epstein-Barr virus-associated post-transplant lymphoproliferative disease with a remarkably late onset in addition to hypogammaglobulinaemia.
- Published
- 2003
- Full Text
- View/download PDF
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