DOCSLIB.ORG

Article Association Between Genotype and Phenotype in Uromodulin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Article Association Between Genotype and Phenotype in Uromodulin Article Association between Genotype and Phenotype in Uromodulin-Associated Kidney Disease Jonathan L. Moskowitz,* Sian E. Piret,† Karl Lhotta,‡§ Thomas M. Kitzler,| Adam P. Tashman,* Erin Velez,* Rajesh V. Thakker,† and Peter Kotanko* Summary Background and objectives Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by uromodulin (UMOD) gene mutations. This study explored genotype-phenotype correlations by ex- *Renal Research Institute, New York, amining the relationship between the type of UMOD mutation and the age at onset of ESRD. New York; †Academic Endocrine Unit, Design, setting, participants & measurements Extensive bibliographic research was used to ascertain patient-level Radcliffe Department of Medicine, Oxford data of all patients with UAKD published up to October 2011. Data included sex; ages at onset of hyperuricemia, fi Centre for Diabetes, gout, and ESRD; and UMOD genotype. Kaplan-Meier analysis and Cox proportional hazards models tted with Endocrinology and shared gamma frailty terms to adjust for within-family correlations were used to model time to event. Metabolism, Churchill Hospital, University of Oxford, Oxford, Results Thirty-one peer-reviewed publications reporting on 202 patients from 74 families with 59 different United Kingdom; UMOD mutations were included. Median ages at onset of hyperuricemia, gout, and ESRD were 24, 40, and 56 ‡Department of years, respectively. Men developed gout and ESRD significantly earlier than did women (age at ESRD was 50 Nephrology and years for men and 60 for women; P=0.04, shared frailty model). Median ages at ESRD development were lowest Dialysis and §Vorarlberg Institute with Cys77Tyr (37.5 years) and highest with Gln316Pro (65.5 years) UMOD mutations. Onset of ESRD was fi for Vascular signi cantly earlier with UMOD mutations located within the epidermal growth factor domains 2 and 3 (range, Investigation and 45–52 years; P,0.01 and 0.04, respectively) compared with the cysteine-rich domains (range, 60–65 years; by Treatment, Academic shared frailty model). Teaching Hospital Feldkirch, Feldkirch, | fi Austria; and Division Conclusions The UMOD genotype is related to the clinical phenotype of UAKD. This nding may assist in of Medical Genetics, counseling of patients. McGill University Clin J Am Soc Nephrol 8: 1349–1357, 2013. doi: 10.2215/CJN.11151012 Health Centre, Montreal, Quebec, Canada fi Introduction UMOD is rst synthesized as an 84-kD precursor, Correspondence: Dr. Uromodulin (UMOD) is encoded by the UMOD gene then slowly converted into the mature 95-kD 640– Peter Kotanko, Renal on chromosome 16p12 and is the most abundant pro- amino acid glycoprotein. UMOD mutations present Research Institute, tein found in human urine (1). UMOD is postulated in patients with UAKD cause a delay in the matura- 207 East 94th Street, to affect urine concentration by maintaining tubular Suite 303, New York, tion rate and protein export to the plasma membrane NY 10128. Email: water impermeability and regulating salt transport because of a longer retention time in the endoplasmic [email protected] (2,3). More recent research suggests it can also acti- reticulum (7–12). It is possible that mutations that vate dendritic cells to express proinflammatory cyto- differentially affect the rate of UMOD maturation kines and thereby possibly promote inflammation in and expression on the cellular membrane can influ- the renal interstitium (4). Uromodulin-associated kid- ence the clinical course of the disease. Most UMOD ney disease (UAKD) refers to autosomal dominant mutations cluster in exons 4 and 5 and cause changes interstitial kidney disease. Mutations in the UMOD to cysteine residues, which leads to a misfolding of gene were found to be associated with clinical man- the UMOD molecule (1). ifestations, such as hyperuricemia, gout, and CKD (5). UMOD contains three epidermal growth factor Different diagnoses were given to patients with these (EGF) domains; a cysteine-rich region, which conditions, which were also found to have mutations includes a domain of eight cysteines (D8C); and a in the UMOD gene (e.g., medullary cystic kidney dis- zona pellucida domain (12) (Supplemental Figure 1 ease type 2, familial juvenile hyperuricemic nephrop- and Supplemental Table 1). Exons 4 and 5 encode the athy, hereditary nephropathy with hyperuricemia first EGF domain to the end of the cysteine-rich re- and gout, uromodulin storage disease, and glomeru- gion. Mutations in each region have been found with locystic kidney disease). However, it has been pro- varying levels of clinical phenotype severity. Muta- posed that a clinical distinction among these terms tions that reduce the calcium-binding affinity in the is not warranted because they appear to represent a calcium-binding EGF (cbEGF) domain may impair spectrum of one and the same disease (6). global protein structure (7). Bound calcium stabilizes www.cjasn.org Vol 8 August, 2013 Copyright © 2013 by the American Society of Nephrology 1349 1350 Clinical Journal of the American Society of Nephrology the cbEGF-like domain conformation, restricting interdo- defined as first diagnosis of serum uric acid level .1SD main flexibility (13), and may protect against proteolytic greater than normal values for age and sex (16). Age at degradation (14). gout onset was defined as the patient’sageatthefirst Families with UMOD mutations have been identified in episode of gouty arthritis. the United States, Austria, Spain, France, Portugal, the Czech Republic, the United Kingdom, Belgium, Germany, Statistical Analyses Switzerland, Latvia, Morocco, Japan, Turkey, and South The primary aim of the study was to explore the relation- Korea. However, there has not been a worldwide epide- ship between UMOD mutations and time to ESRD. Second- miologic study on UAKD. This analysis strives to ascertain ary aims were to analyze the relationships between sex and all UAKD cases published through October 2011 and to age at the onset of hyperuricemia and gout. To that end, relate UMOD genotype to clinical presentation. median age at the onset of hyperuricemia, gout, and ESRD were computed. In separate analyses, patients were strati- fied by sex, presence or absence of hyperuricemia or gout, Materials and Methods UMOD mutation, affected uromodulin domain, and cell Search Strategy surface expression pattern. Extensive electronic and manual bibliographic research The six UMOD mutations with the most affected indi- was performed to ascertain patient-level data of all cases of viduals were examined to determine whether having a dif- UAKD published through October 2011. Meticulous care ferent genotype could affect the outcome. In an additional was exercised to exclude duplicate reports of patients. We analysis, UMOD mutations were aggregated according to reviewed citations in English from PubMed, the D. Samuel their place within one of the five following functional do- Gottesman Library from the Albert Einstein College of mains: CysRich-1, CysRich-2, D8C, EGF2, and EGF3. Only Medicine in New York, and Google Scholar. The search functional domains with mutations affecting more than 14 strategy included keywords and synonyms for the follow- patients were considered. Mutations were further classi- ing terms: familial juvenile hyperuricemic nephropathy, fied into groups in which substitutions affected a cysteine uromodulin, Tamm-Horsfall protein, medullary cystic residue, a nonpolar residue, and a noncysteine polar resi- kidney disease, mutation, uric acid, gout, and hyperurice- due. Cysteine substitutions were then compared with non- mia. Full-text articles were retrieved for further indepen- cysteine substitutions. dent manual evaluation by two authors (J.M. and E.V.). For the modeling process, statistical adjustments for Supplemental searches using the names of authors of members of the same family were made. This was done by relevant articles were performed. multiplicatively adjusting the hazard rate of each family All retrieved published full-text case studies on individ- member by the same factor (the frailty) according to the uals and families with UAKD were included. When the model mentioned below. For example, it may be the case same family was investigated in more than one study, the that all members of family A are frailer than members of most recent study with the most thorough data were family B, adjusting for other covariates. In this case, the included. If the most recent publication had incomplete family A frailty will be greater than the family B frailty. clinical data, the data were combined with a previous study The gamma shared frailty model—which is an extension and adjusted for time. In some instances, authors were of the Cox model—was used to estimate hazard ratios fi personally contacted for data veri cation. In addition, one (17,18). If the frailty effect was not statistically significant hitherto unpublished UAKD family was included. A search at 0.05, it was excluded and a conventional Cox propor- for UMOD mutations in the 1000 Genomes database tional hazard model was used to fittothedata.TheR showed that UAKD-associated mutations were not detec- package survival was used to fit the models and perform fi ted in that population, con rming the rare, pathogenic na- hypothesis testing (19). ture of the UMOD mutations studied here. Allele Additionally, in models with significant frailty effect, the frequency variation across different populations is there- shared frailty model was used to estimate median time to fore an unlikely confounding factor. event and the 95% confidence interval (CI) around the median. The median can be computed for any given frailty, Data Ascertainment and here a value of unity was used (this assumes that the Articles were scanned for information on all patients individual has average frailty). For case frailty = 1, the reported. All clinical data were recorded in a database, formula for the median under the shared frailty model is including pedigree position, sex, race, country of residence, the same as the formula for the median under the Cox type of UMOD mutation, ESRD status, age at hyperurice- model, but the latter must use the parameter estimates from mia, gout, ESRD, death, and age at last follow-up.
Load more

Recommended publications
  • Label-Free Proteomic Methodology for the Analysis of Human Kidney Stone Matrix Composition Frank A
    Witzmann et al. Proteome Science (2016) 14:4 DOI 10.1186/s12953-016-0093-x METHODOLOGY Open Access Label-free proteomic methodology for the analysis of human kidney stone matrix composition Frank A. Witzmann1*, Andrew P. Evan2, Fredric L. Coe3, Elaine M. Worcester3, James E. Lingeman4 and James C. Williams Jr2 Abstract Background: Kidney stone matrix protein composition is an important yet poorly understood aspect of nephrolithiasis. We hypothesized that this proteome is considerably more complex than previous reports have indicated and that comprehensive proteomic profiling of the kidney stone matrix may demonstrate relevant constitutive differences between stones. We have analyzed the matrices of two unique human calcium oxalate stones (CaOx-Ia and CaOx-Id) using a simple but effective chaotropic reducing solution for extraction/solubilization combined with label-free quantitative mass spectrometry to generate a comprehensive profile of their proteomes, including physicochemical and bioinformatic analysis.` Results: We identified and quantified 1,059 unique protein database entries in the two human kidney stone samples, revealing a more complex proteome than previously reported. Protein composition reflects a common range of proteins related to immune response, inflammation, injury, and tissue repair, along with a more diverse set of proteins unique to each stone. Conclusion: The use of a simple chaotropic reducing solution and moderate sonication for extraction and solubilization of kidney stone powders combined with label-free quantitative mass spectrometry has yielded the most comprehensive list to date of the proteins that constitute the human kidney stone proteome. Keywords: Calcium oxalate, Kidney stone, Label-free quantitative liquid chromatography–tandem mass spectrometry, Matrix protein, Nephrolithiasis, Proteomics Background deposition is the primary event, at least in the formation The organic matrix within urinary stones has long been of CaOx stones over plaque.
    [Show full text]
  • Uromodulin Levels Associate with a Common UMOD Variant and Risk for Incident CKD
    CLINICAL EPIDEMIOLOGY www.jasn.org Uromodulin Levels Associate with a Common UMOD Variant and Risk for Incident CKD ʈ ʈ Anna Ko¨ttgen,* Shih-Jen Hwang,†‡ Martin G. Larson,§ Jennifer E. Van Eyk, Qin Fu, Emelia J. Benjamin,†¶ Abbas Dehghan,** Nicole L. Glazer,†† W.H. Linda Kao,* ʈʈ Tamara B. Harris,‡‡ Vilmundur Gudnason,§§ Michael G. Shlipak,¶¶ Qiong Yang,§ Josef Coresh,* Daniel Levy,†‡ and Caroline S. Fox†‡*** *Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; †Framingham Heart Study, Framingham, Massachusetts; ‡Center for Population Studies, National Heart, Lung, and Blood Institute, and ‡‡Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland; Departments of §Biostatistics and ʈ ¶Epidemiology, Boston University School of Public Health, Boston, Massachusetts; Department of Medicine, Johns Hopkins University, Baltimore, Maryland; **Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; ††Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, ʈʈ Washington; §§Icelandic Heart Association Research Institute, Kopavogur, Iceland; University of Iceland, Reykjavik, Iceland; ¶¶General Internal Medicine Division, San Francisco VA Medical Center, University of California, San Francisco, California; and ***Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts ABSTRACT Common variants in the region of the UMOD gene, which encodes uromodulin (Tamm-Horsfall protein), associate with chronic kidney disease (CKD) and estimated GFR (eGFR). Whether uromodulin levels associate with UMOD variants or with the risk for developing CKD is unknown. We conducted an age- and gender- matched case-control study (n ϭ 200) of incident CKD (eGFR Ͻ60 ml/min per 1.73 m2) within the Framingham Heart Study (FHS).
    [Show full text]
  • Autosomal Dominant Tubulointerstitial Kidney Disease Genotype And
    www.nature.com/scientificreports OPEN Autosomal dominant tubulointerstitial kidney disease genotype and phenotype correlation in a Chinese cohort Kunjing Gong1,2,3,4, Min Xia1,2,3,4, Yaqin Wang1,2,3,4, Na Wang1,2,3,4, Ying Liu1,2,3,4, Victor Wei Zhang5,6, Hong Cheng 7 & Yuqing Chen1,2,3,4* Genes of UMOD, HNF1B, MUC1, REN and SEC61A1 were reported to be associated with autosomal dominant tubulointerstitial kidney disease (ADTKD). 48 probands and their family members (N = 27) were enrolled in this genetic screening study. A combination of methods was employed for comprehensive molecular analysis of both copy number variations (CNVs) and single nucleotide variants (SNVs). 35 probands were followed for years. The phenotype-genotype and genotype- outcome correlation were inferred from these datasets. In this cohort, 18 probands were diagnosed with ADTKD, according to Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Moreover, 11 probands were diagnosed with ADTKD-UMOD, one with ADTKD-REN and one with ADTKD-HNF1B, based on molecularly confrmed pathogenic variants. The 11 UMOD variants were mainly located in codons 28 to 289 and half of the variants were found to change the cysteine amino acid. According to the follow-up data, suspected ADTKD individuals had a better prognosis compared to ADTKD individuals (p = 0.029). Individuals with a cysteine substitution in the UMOD gene appeared to have a better prognosis than individuals with other amino acid substitutions (p = 0.015). Autosomal dominant tubulointerstitial kidney disease (ADTKD) is considered to be one of the common causes of end stage renal disease (ESRD), especially in people whereby familial aggregation is observed1.
    [Show full text]
  • Uromodulin-Associated Kidney Disease
    Uromodulin-associated kidney disease Description Uromodulin-associated kidney disease is an inherited condition that affects the kidneys. The signs and symptoms of this condition vary, even among members of the same family. Many individuals with uromodulin-associated kidney disease develop high blood levels of a waste product called uric acid. Normally, the kidneys remove uric acid from the blood and transfer it to urine. In this condition, the kidneys are unable to remove uric acid from the blood effectively. A buildup of uric acid can cause gout, which is a form of arthritis resulting from uric acid crystals in the joints. The signs and symptoms of gout may appear as early as a person's teens in uromodulin-associated kidney disease. Uromodulin-associated kidney disease causes slowly progressive kidney disease, with the signs and symptoms usually beginning during the teenage years. The kidneys become less able to filter fluids and waste products from the body as this condition progresses, resulting in kidney failure. Individuals with uromodulin-associated kidney disease typically require either dialysis to remove wastes from the blood or a kidney transplant between the ages of 30 and 70. Occasionally, affected individuals are found to have small kidneys or kidney cysts (medullary cysts). Frequency The prevalence of uromodulin-associated kidney disease is unknown. It accounts for fewer than 1 percent of cases of kidney disease. Causes Mutations in the UMOD gene cause uromodulin-associated kidney disease. This gene provides instructions for making the uromodulin protein, which is produced by the kidneys and then excreted from the body in urine.
    [Show full text]
  • ASN Kidney Week 2019
    ONSITE GUIDE 20 19 Washington, DC Nov. 5–10 CORPORATE SUPPORTERS The ASN Corporate Support Program recognizes supporters year round for their generous contributions to the Society. Through this program, supporters help ASN lead the fight against kidney diseases. ASN gratefully acknowledges the following companies and organizations for their contributions in 2019. DIAMOND LEVEL PLATINUM LEVEL GOLD LEVEL Akebia Therapeutics OPKO Pharmaceuticals, LLC Amgen Retrophin, Inc. Janssen Pharmaceuticals, Inc. BRONZE LEVEL Amicus Therapeutics KDIGO Cara Therapeutics Rockwell Medical Daiichi Sankyo, Inc. Sanofi Genzyme GSK As of August 19, 2019 TABLE OF CONTENTS Kidney Week Mobile App 3 Schedule-at-a-Glance 4 Welcome 6 Accreditation, CE Credits, MOC Points 7 Certificates of Attendance for International Participants 8 Day-at-a-Glance: Tuesday, November 5 10 Day-at-a-Glance: Wednesday, November 6 12 Day-at-a-Glance: Thursday, November 7 14 Day-at-a-Glance: Friday, November 8 32 Day-at-a-Glance: Saturday, November 9 50 Scientific Exposition 64 Exhibitor Spotlights 66 Day-at-a-Glance: Sunday, November 10 69 Attention US Physicians To ensure full compliance with the Open Payments (Physician Payments Sunshine Act), a provision of the Patient Protection and Affordable Care Act (PL 111-148), ASN reserves the right to provide information to applicable manufacturers and applicable GPOs about US physicians (and their spouses) who participate in selected ASN activities. Section 6002 of the Affordable Care Act requires the establishment of a transparency program, now known as Open Payments. The program increases public awareness of financial relationships between drug and device manufacturers and certain healthcare providers.
    [Show full text]
  • A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin
    J Am Soc Nephrol 14: 2883–2893, 2003 A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin KARIN DAHAN,* OLIVIER DEVUYST,† MICHE` LE SMAERS,* DIDIER VERTOMMEN,† GUY LOUTE,§ JEAN-MICHEL POUX,ʈ BE´ ATRICE VIRON,¶ CHRISTIAN JACQUOT,# MARIE-FRANCE GAGNADOUX,** DOMINIQUE CHAUVEAU,†† MATHIAS BU¨ CHLER,‡‡ PIERRE COCHAT,§§ JEAN-PIERRE COSYNS,ʈʈ BE´ ATRICE MOUGENOT,¶¶ MARK H. RIDER,‡ CORINNE ANTIGNAC,## CHRISTINE VERELLEN-DUMOULIN*, and YVES PIRSON† *Université Catholique de Louvain, Center for Human Genetics, Brussels, Belgium; †Université Catholique de Louvain, Division of Nephrology, Brussels, Belgium; ‡Université Catholique de Louvain, International Institute of Cellular and Molecular Pathology, HORM Unit, Brussels, Belgium; §Hôpital Princesse Paola, Department of Nephrology, Aye, Belgium; ʈHôpital de Frejus, Department of Nephrology, Frejus, France; ¶Hôpital Bichat-Claude Bernard, Department of Nephrology, Paris, France; #Hôpital Georges Pompidou, Department of Nephrology, Paris, France; **Hôpital Necker, Department of Pediatric Nephrology, Paris, France; ††Hôpital Necker, Department of Nephrology and INSERM U507, Paris, France; ‡‡Centre Hospitalier Régional, Department of Nephrology, Tours, France; §§Hôpital Edouard Herriot, Department of Pediatric Nephrology, Lyon, France; ʈʈUniversité Catholique de Louvain, Department of Pathology, Brussels, Belgium; ¶¶Hôpital Tenon, Department of Pathology, Paris, France; and ##Université Paris V, Necker Hospital, INSERM U574, and Department of Genetics, Paris, France Abstract. Familial juvenile hyperuricemic nephropathy (FJHN consequences of UMOD mutations on uromodulin expression [MIM 162000]) is an autosomal-dominant disorder characterized were investigated in urine samples and renal biopsies from nine by abnormal tubular handling of urate and late development of patients in four families. There was a markedly increased expres- chronic interstitial nephritis leading to progressive renal failure.
    [Show full text]
  • The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation Through Human Evolution
    BRIEF COMMUNICATION www.jasn.org The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution † ‡ Silvia Ghirotto,* Francesca Tassi,* Guido Barbujani,* Linda Pattini, Caroline Hayward, | Peter Vollenweider,§ Murielle Bochud,§ Luca Rampoldi, and Olivier Devuyst¶ *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; †Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy; ‡Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; §Department of Internal Medicine, Institute of Social and Preventive Medicine, Lausanne University Hospital Center, Lausanne, Switzerland; |Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and ¶Institute of Physiology, University of Zurich, Zurich, Switzerland ABSTRACT Common variants in the UMOD gene encoding uromodulin, associated with risk and in mouse models of autosomal dom- of hypertension and CKD in the general population, increase UMOD expression inant tubulointerstitial kidney disease and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal revealed intracellular aggregates of mu- lesions. To determine the effect of selective pressure on variant frequency, we in- tant uromodulin in the TAL cells, coupled vestigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human with a systematic decrease of uromodulin populations, in eight ancient human genomes, and in primate genomes. The T allele excretion in the urine.9–11 of rs4293393, associated with CKD risk, has high frequency in most modern popu- In parallel, multiple genome-wide lations and was the one detected in primate genomes. In contrast, we identified association studies (GWAS) and se- only the derived, C allele in Denisovan and Neanderthal genomes.
    [Show full text]
  • The Cryo-EM Structure of the Human Uromodulin Filament Core Reveals A
    SHORT REPORT The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism Jessica J Stanisich1†, Dawid S Zyla1†, Pavel Afanasyev2, Jingwei Xu1, Anne Kipp3, Eric Olinger4, Olivier Devuyst3,5, Martin Pilhofer1, Daniel Boehringer2, Rudi Glockshuber1* 1Institute of Molecular Biology & Biophysics, ETH Zurich, Zurich, Switzerland; 2Cryo- EM Knowledge Hub (CEMK), ETH Zurich, Zurich, Switzerland; 3Institute of Physiology, University of Zurich, Zurich, Switzerland; 4Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom; 5Division of Nephrology, UCLouvain Medical School, Brussels, Belgium Abstract The glycoprotein uromodulin (UMOD) is the most abundant protein in human urine and forms filamentous homopolymers that encapsulate and aggregate uropathogens, promoting pathogen clearance by urine excretion. Despite its critical role in the innate immune response against urinary tract infections, the structural basis and mechanism of UMOD polymerization remained unknown. Here, we present the cryo-EM structure of the UMOD filament core at 3.5 A˚ resolution, comprised of the bipartite zona pellucida (ZP) module in a helical arrangement with a rise of ~65 A˚ and a twist of ~180˚. The immunoglobulin-like ZPN and ZPC subdomains of each monomer are separated by a long linker that interacts with the preceding ZPC and following ZPN *For correspondence: subdomains by b-sheet complementation. The unique filament architecture suggests
    [Show full text]
  • Tamm-Horsfall Protein Is a Critical Renal Defense Factor Protecting Against Calcium Oxalate Crystal Formation
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 66 (2004), pp. 1159–1166 Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation LAN MO,HONG-YING HUANG,XIN-HUA ZHU,ELLEN SHAPIRO,DAVID L. HASTY, and XUE-RU WU Department of Urology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York; Department of Microbiology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York; Veterans Affairs Medical Center, New York, New York; Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee; and Veterans Affairs Medical Center, Memphis, Tennessee Tamm-Horsfall protein is a critical renal defense factor protect- Renal stone disease or nephrolithiasis is an exceedingly ing against calcium oxalate crystal formation. common clinical condition in the industrialized world. Up Background. The tubular fluid of the mammalian kidney is of- to 15% of white males and 6% of all females will have ten supersaturated with mineral salts, but crystallization rarely occurs under normal conditions. The unique ability of the kid- at least one renal stone during their lifetime, and half ney to avoid harmful crystal formation has long been attributed of these individuals will experience recurrence [1, 2]. In to the inhibitory activity of the urinary macromolecules, al- the United States, the disease afflicts more than 1 million though few in vivo studies have been carried out to examine people annually and accounts for nearly 10 of every 1000 this hypothesis.
    [Show full text]
  • Overexpression of Uromodulin-Like1 Accelerates Follicle Depletion and Subsequent Ovarian Degeneration
    Citation: Cell Death and Disease (2012) 3, e433; doi:10.1038/cddis.2012.169 & 2012 Macmillan Publishers Limited All rights reserved 2041-4889/12 www.nature.com/cddis Overexpression of Uromodulin-like1 accelerates follicle depletion and subsequent ovarian degeneration W Wang*,1, Y Tang1,LNi1, E Kim1, T Jongwutiwes1, A Hourvitz2, R Zhang3, H Xiong3, H-C Liu1 and Z Rosenwaks1 Murine Uromodulin-like 1 (Umodl1) encodes Ca2 þ -dependent EGF-like membrane-bound proteins. This study presents its novel expression in the immune and female reproductive systems. Upon stimulation by CD3/CD28 antibodies, Umodl1 showed a prompt and robust response in the proliferating CD4 þ T cells, suggesting its implication in immune defense against pathogens. In ovary, Umodl1 is regulated by gonadotropins. Mice carrying extra copies of functional Umodl1 were generated by BAC transgenesis. Defects in the female reproductive system became evident from 4 months of age, manifested by reduced or diminished fertility. Histology revealed that the ovaries contained very few discernible follicles in the cortical region, and were devoid of distinguishable corpus lutea (CL). Among the multilayered preantral follicles, elevated apoptosis was observed in both the oocytes and surrounding granulosa cells (GCs). Furthermore, a high level of PPARc indicated an abnormal adipogenesis in the mutant ovaries, which resulted in the conversion of GCs into adipocytes. By 6 months of age, all mutant mice became anovulatory. Ovarian tissues including CL, follicles of various stages and associated stromal cells were degenerated. Altered expression of AMH, follicle-stimulating hormone and other ovary-specific marker genes such as Gdf-9, Rnf35, NOHLH and Gcx-1 further demonstrated that the molecular properties of the mutant ovaries have been severely disturbed.
    [Show full text]
  • Defective Intracellular Trafficking of Uromodulin Mutant Isoforms
    # 2006 The Authors Traffic 2006; 7: 1–13 Blackwell Munksgaard doi: 10.1111/j.1600-0854.2006.00481.x Defective Intracellular Trafficking of Uromodulin Mutant Isoforms Ilenia Bernascone1,†, Stefano Vavassori1,†, Key words: chronic renal diseases, ER retention, familial Alessio Di Pentima2, Sara Santambrogio1, juvenile hyperuricemic nephropathy, medullary cystic 3 4 kidney disease, protein trafficking, Tamm–Horsfall pro- Giuseppe Lamorte , Antonio Amoroso , tein, uromodulin Francesco Scolari5, Gian Marco Ghiggeri6, Giorgio Casari7, Roman Polishchuk2 and Received 30 April 2006, revised and accepted for publica- Luca Rampoldi1,* tion 26 July 2006 1Dulbecco Telethon Institute, DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy 2Department of Cell Biology and Oncology, Istituto di Uromodulin is the most abundant protein in human urine Ricerche Farmacologiche Mario Negri, Via Nazionale, under physiological conditions, being excreted at a rate of 66030 Santa Maria Imbaro, Chieti, Italy 50–100 mg per day (1). It was initially characterized by 3Biotechnology and Biosciences Department, Tamm and Horsfall in 1950 (2), and it is also referred to University of Milan Bicocca, Piazza della Scienza 2, as Tamm–Horsfall protein. Uromodulin is found in urine 20126 Milan, Italy 6 4Department of Genetics, Biology and Biochemistry, as a high-molecular-weight polymer (Mr 1–10 Â 10 ) that University of Turin, Via Santena 19, 10126 Turin, Italy can be dissociated into monomers of about 95 kDa (3). 5Division of Nephrology, Spedali Civili and University of It is a glycoprotein with seven out of eight potential N- Brescia, Piazzale Spedali Civili 1, 25125 Brescia, Italy glycosylation sites being glycosylated; N-glycans account 6 Laboratory on Pathophysiology of Uremia, G.
    [Show full text]
  • Mechanism of Injury in Uromodulin-Associated Kidney Disease
    Editorial Mechanism of Injury in Uromodulin-Associated Kidney Disease Satish Kumar Division of Nephrology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma J Am Soc Nephrol 18: 10–12, 2007. doi: 10.1681/ASN.2006111234 ephronophthisis (NPHP), medullary cystic kidney Since then, several additional families have been described. Its disease (MCKD), and familial juvenile hyperurice- clinical and histologic features are similar to those of MCKD N mic nephropathy (FJHN) are three renal disorders type 2. In most but not all families with FJHN, genetic studies with overlapping clinical features. Recent molecular genetic have revealed mutations in the UMOD gene. Patients with studies have begun to clarify the similarities and differences FJHN who do not have UMOD mutations still show decreased between these conditions. Moreover, the pathogenetic mecha- THP excretion in urine, which suggests involvement of a pro- nisms of renal damage in these conditions are being clarified. In tein involved in THP processing (19). A consensus is emerging this issue of JASN, Jennings et al. (1) present one such study. in the literature that FJHN and MCKD type 2 are the same A syndrome first described in 1945 (2) was named NPHP by disease (20,21). Fanconi et al. in 1951 (3). Characteristic findings include renal THP is urine’s most abundant protein (12–15). It is synthe- tubular atrophy, interstitial fibrosis, corticomedullary cysts, sized exclusively and abundantly in the thick ascending limb of and progressive renal failure (4). Gout is not a known feature. the loop of Henle. Its biologic function remains somewhat NPHP, unlike MCKD and FJHN, is inherited as an autosomal unclear more than a century after its first description in 1895 recessive trait.
    [Show full text]