MUC1 – Autosomal Dominant Medullary Cystic Kidney Disease with or without Hyperuricemia

Autosomal dominant tubulointerstitial kidney disease due to pathogenic MUC1 variants (ADTKD-MUC1) is characterized by progressive chronic kidney disease presenting in adolescence or adulthood, bland urinary sediment, hyperuricemia and gout in some patients, and a family history consistent with autosomal dominant inheritance. MUC1 was identified as the causal gene for ADTKD-MUC1 through the discovery of a recurrent single cytosine insertion in the GC-rich VNTR region, which leads to a frameshift and production of a mutant protein (MUC1fs) that aggregates in renal tubular cells ([PMID:29156055]).

Genetic evidence for the MUC1–ADTKD association is strong. In two large registries encompassing 585 families with presumptive ADTKD, 4 distinct MUC1 frameshift mutations were found in 72 of 205 UMOD-negative families, accounting for 83 affected individuals across 72 unrelated pedigrees (83 probands) ([PMID:32450155]). An independent observational cohort using VNtyper identified 33 new index cases and 7 affected relatives segregating MUC1 VNTR pathogenic variants, confirming segregation in extended families (7 relatives) ([PMID:39848530]).

Functional studies demonstrate that the MUC1fs protein is mislocalized and self-aggregates in the cytoplasm of tubular cells. Recombinant MUC1fs constructs showed cytoplasmic retention and impaired secretion, mirroring the native mutant protein detected in urinary exosomes of affected patients ([PMID:29156055]). Noninvasive immunohistochemical staining using MUC1fs-specific antibodies reliably distinguishes ADTKD-MUC1 in urinary cell smears and kidney biopsy specimens, supporting a proteinopathy mechanism ([PMID:29967284]).

Pathogenic MUC1 variants act via a toxic gain-of-function protein aggregation mechanism leading to tubular atrophy and interstitial fibrosis. The cytoplasmic accumulation of MUC1fs triggers cellular stress pathways, although the precise downstream effectors remain under investigation. No conflicting evidence has been reported to date.

Clinically, ADTKD-MUC1 diagnosis has been hindered by the VNTR gene structure, which resists standard short-read sequencing. Recent advances, including SNaPshot minisequencing, long-read sequencing, and computational pipelines (VNtyper), now allow routine detection of MUC1fs variants. Detection of MUC1fs in urine exosomes and tissue immunostaining offers a non-DNA diagnostic avenue, facilitating genetic counseling and early clinical management.

Key Take-home: Pathogenic MUC1 VNTR frameshift mutations cause a definitive autosomal dominant tubulointerstitial kidney disease via a protein aggregation mechanism, and novel molecular and immunohistochemical tools enable accurate diagnosis for clinical and research applications.

References

• Nephrology, dialysis, transplantation • 2017 • Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein. PMID:29156055
• Kidney international • 2020 • Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1 PMID:32450155
• Journal of the American Society of Nephrology • 2018 • Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease. PMID:29967284
• American journal of kidney diseases • 2025 • Phenotypic Heterogeneity of ADTKD-MUC1 Diagnosed Using VNtyper, a Novel Genetic Technique. PMID:39848530

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