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Autosomal dominant tubulointerstitial kidney disease with a novel heterozygous missense mutation in the uromodulin gene: A case report.

ABSTRACT: BACKGROUND:Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a progressive chronic disease that is inherited in an autosomal dominant fashion. Symptoms include hyperuricemia, gout, interstitial nephritis, renal cysts, and progressive renal damage that can lead to end-stage renal disease. Mutations in the uromodulin gene (UMOD) characterize the ADTKD-UMOD clinical subtype of this disease. To date, > 100 UMOD mutations have been identified. Early diagnosis of ADTKD-UMOD is important to treat the disease, slow down disease progression, and facilitate the identification of potentially affected family members. CASE SUMMARY:We report a 40-year-old man harboring a novel heterozygous missense mutation in UMOD (c.554G>T; p. Arg185Leu). The patient had hyperuricemia, gout, and chronic kidney disease. The same mutation was detected in his daughter, aunt and cousin. CONCLUSION:A single nucleotide substitution in exon 3 of UMOD was responsible for the heterozygous missense mutation (c.554G>T, p.Arg185Leu).

SUBMITTER: Zhang LL

PROVIDER: S-EPMC8638067 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Allelic Effects on Uromodulin Aggregates Drive Autosomal Dominant Tubulointerstitial Kidney Disease

Project description:Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain-of-function mutations, end-organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated UmodC171Y and UmodR186S knock-in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild-type Umod allele in heterozygous UmodR186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation-specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD-UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin.

| S-SCDT-10_15252-EMMM_202318242 | biostudies-other

Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

Project description:Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD mutations is characterized by strong interfamilial variability. We generated two mutant Umod knock-in mouse models, harbouring two mutations associated with drastic differences in kidney survival in ADTKD patients. We performed bulk RNA-sequencing of kidney extracts from Umod KI mice at an early (1 month) and advanced (4 months) stage of disease.

2022-10-02 | GSE214491 | GEO

Autosomal Dominant Tubulointerstitial Kidney Disease-Uromodulin Misclassified as Focal Segmental Glomerulosclerosis or Hereditary Glomerular Disease.

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Autosomal dominant tubulointerstitial kidney disease: A review.

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The First Pediatric Case of an IFT140 Heterozygous Deletion Causing Autosomal Dominant Polycystic Kidney Disease: Case Report.

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Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland.

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Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

Project description:Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

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A case of familial juvenile hyperuricemic nephropathy with novel uromodulin gene mutation, a novel heterozygous missense mutation in Korea.

Project description:Familial Juvenile hyperuricemic nephropathy (FJHN, OMIM #162000) is a rare autosomal dominant disorder characterized by hyperuricemia with renal uric acid under-excretion, gout and chronic kidney disease. In most but not all families with FJHN, genetic studies have revealed mutations in the uromodulin (UMOD) gene located on chromosome 16p11-p13. We here described a novel heterozygous missense mutation (c.1382C>A causing p.Ala461Glu) in an affected 16-year-old male with hyperuricemia, gout and chronic kidney disease. His father was also affected and the UMOD mutation was found to segregate with the disease. There has been only one case report of Korean family with FJHN, which has not been diagnosed by genetic study. This is the first report of genetically diagnosed FJHN in Korea.

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A novel missense mutation in the ACTG1 gene in a family with congenital autosomal dominant deafness: A case report.

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