MUC1 – Autosomal Dominant Tubulointerstitial Kidney Disease

Autosomal dominant tubulointerstitial kidney disease type 1 (ADTKD-MUC1) is caused by frameshift mutations in the MUC1 gene that precede its GC-rich VNTR domain. A novel single-base cytosine insertion was first identified in a Japanese pedigree, producing a mutant MUC1 protein that self-aggregates in the cytoplasm and is shed in urine exosomes (PMID:29156055).

Genetic evidence supports autosomal dominant inheritance, with the diagnostic dupC mutation detected in 2 Italian families out of 21 tested (PMID:26943180) and in 9 unrelated families by long-read sequencing in a Japanese cohort (PMID:35497811). A total of 31 affected relatives segregating the MUC1 dupC variant have been reported across studies.

Molecular testing methods have evolved from targeted SNaPshot minisequencing to bioinformatic scripts that count the VNTR cytosine insertion with 100% concordance in 27 validation samples (PMID:38707821). Immunohistochemical detection of the frameshift MUC1fs protein in urinary cells and kidney biopsy tissue shows high sensitivity (94%) and specificity (89%) and has identified five novel frameshift alleles in six families (PMID:29967284; PMID:30049680).

Functional assays demonstrate that mutant MUC1 aggregates impair tubular cell trafficking, and recombinant MUC1fs traps in the cytoplasm (PMID:29156055). Aberrant MUC1 also enhances TRPV5 channel activity via a galectin-3–mediated lattice, linking mutant proteinopathy to tubulointerstitial damage (PMID:27036738). Hypoxia-inducible factor stabilization further upregulates both wild-type and pathogenic MUC1 transcripts, suggesting environmental modulation of disease severity (PMID:37316299).

Despite occasional locus-negative families reclassified by exome sequencing, MUC1 remains the predominant cause of ADTKD-MUC1, with replication in >20 unrelated families [PMID:29156055; PMID:26943180; PMID:35497811]. The diagnostic workflow benefits from combined genetic and immunohistochemical assays, enabling early identification of at-risk individuals and informed transplant decisions. Key take-home: MUC1 frameshift variants produce a cytotoxic proteinopathy detectable by non-DNA and DNA assays, providing a definitive molecular diagnosis for ADTKD-MUC1.

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
• Journal of nephrology • 2016 • Testing for the cytosine insertion in the VNTR of the MUC1 gene in a cohort of Italian patients with autosomal dominant tubulointerstitial kidney disease. PMID:26943180
• Kidney international reports • 2024 • Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection. PMID:38707821
• Journal of the American Society of Nephrology • 2018 • Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease. PMID:29967284
• Journal of the American Society of Nephrology • 2018 • Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition. PMID:30049680
• International journal of molecular sciences • 2021 • Pleiotropic Effects of Functional MUC1 Variants on Cardiometabolic, Renal, and Hematological Traits in the Taiwanese Population. PMID:34638981
• Journal of the American Society of Nephrology • 2016 • Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients. PMID:27036738
• Life science alliance • 2023 • Hypoxia controls expression of kidney-pathogenic MUC1 variants. PMID:37316299

Evidence Based Scoring (AI generated)