UMOD – familial juvenile hyperuricemic nephropathy type 1

The UMOD gene encodes uromodulin, a GPI-anchored glycoprotein expressed in the thick ascending limb of Henle’s loop. Heterozygous pathogenic variants in UMOD cause autosomal dominant familial juvenile hyperuricemic nephropathy type 1, manifesting with early-onset hyperuricemia, gout, and progressive tubulointerstitial fibrosis leading to chronic kidney disease.

Over 202 affected individuals from 74 independent families have been reported, demonstrating autosomal dominant segregation with variable penetrance (PMID:15558519, PMID:23723338). Segregation analyses confirm variant cosegregation with disease in multigenerational pedigrees.

To date, more than 59 distinct UMOD mutations have been described, predominantly missense substitutions disrupting conserved cysteine residues within epidermal growth factor-like domains; additional variant classes include in-frame indels and premature termination codons. A recurrent founder Cys248Trp variant has been identified in European and Turkish kindreds.

Functional assays in patient renal biopsies and transfected cells demonstrate endoplasmic reticulum retention of mutant uromodulin, reduced urinary secretion, and aberrant intracellular accumulation, supporting a toxic gain-of-function mechanism (PMID:14569098, PMID:15558519).

In vivo, a C148W transgenic mouse model expresses ER-retained uromodulin, recapitulating urinary concentrating defects, tubular atrophy, interstitial fibrosis, and progressive renal impairment, establishing disease causality (PMID:20472742).

ADTKD-UMOD accounts for ~9 per million population and constitutes 56% of autosomal dominant tubulointerstitial kidney disease after ADPKD, highlighting the clinical impact of UMOD testing in CKD patients (PMID:30376835).

Mapping of additional candidate loci on chromosome 1q41 without UMOD involvement underscores the gene’s specificity in familial juvenile hyperuricemic nephropathy type 1 (PMID:16164624).

Integrating robust segregation, diverse mutational spectrum, and consistent functional and animal model data supports a Definitive gene-disease relationship.

Key Take-home: Genetic testing for UMOD variants enables early diagnosis and management of familial juvenile hyperuricemic nephropathy type 1.

References

• American journal of kidney diseases • 2004 • Uromodulin storage diseases: clinical aspects and mechanisms. PMID:15558519
• Clinical journal of the American Society of Nephrology • 2013 • Association between genotype and phenotype in uromodulin-associated kidney disease. PMID:23723338
• Journal of the American Society of Nephrology • 2003 • A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. PMID:14569098
• Human molecular genetics • 2010 • A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure. PMID:20472742
• BMC nephrology • 2018 • Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease. PMID:30376835
• Kidney international • 2005 • Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41. PMID:16164624

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