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A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion.

ABSTRACT: Heterozygous mutations in UMOD encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous UMOD mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.

SUBMITTER: Edwards N

PROVIDER: S-EPMC5837645 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion.

Edwards Noel N Olinger Eric E Adam Jennifer J Kelly Michael M Schiano Guglielmo G Ramsbottom Simon A SA Sandford Richard R Devuyst Olivier O Sayer John A JA

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20171201 12

Heterozygous mutations in UMOD encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous UMOD mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low level ...[more]

PMID: 28605509

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Project description:Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced.Individuals (n?=?485) were selected based on presence of the GWAS risk haplotype and chronic kidney disease (CKD) in the ARIC Study and on the extremes of of the UMOD gene product, uromodulin, in urine (Tamm Horsfall protein, THP) in the Framingham Heart Study (FHS). Targeted sequencing was conducted using capillary based Sanger sequencing (3730 DNA Analyzer). Variants were tested for association with THP concentrations and estimated glomerular filtration rate (eGFR), and identified non-synonymous coding variants were genotyped in up to 22,546 follow-up samples. Twenty-four and 63 variants were identified in the 285 ARIC and 200 FHS participants, respectively. In both studies combined, there were 33 common and 54 rare (MAF<0.05) variants. Five non-synonymous rare variants were identified in FHS; borderline enrichment of rare variants was found in the extremes of THP (SKAT p-value?=?0.08). Only V458L was associated with THP in the FHS general-population validation sample (p?=?9*10(-3), n?=?2,522), but did not show direction-consistent and significant association with eGFR in both the ARIC (n?=?14,635) and FHS (n?=?7,520) validation samples. Pooling all non-synonymous rare variants except V458L together showed non-significant associations with THP and eGFR in the FHS validation sample. Functional studies of V458L revealed no alternations in protein trafficking.Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR in two independent study samples. Only V458L had modest association with THP levels in the general population and thus could not account for the observed GWAS signal.

Dataset Information

A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion.

Publications

A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion.

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