Submission Details

MUC1 was FIRST reported in relation to autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1; OMIM: 174000) in 2013 (Kirby et al, PMID: 23396133). ADTKD-MUC1 is characterized by slowly progressive tubulointerstitial kidney disease that leads to end-stage renal disease (ESRD) between ages 20-70 years. Age of end-stage kidney disease is variable and the reasons for this variability are unclear. Patients with ADTKD-MUC1 have a bland urinary sediment without proteinuria or hematuria. The kidney ultrasound shows changes that are commonly found in chronic kidney disease and in general is not helpful in making this diagnosis. The key diagnostic parameter is a family history of chronic kidney disease. There are no other primary clinical manifestations of this disease (PMIDs: 24509297, 23946964; 32450155, 36250282). MUC1 contains within the coding region a domain of multiple variable-number tandem repeats called the "VNTR domain" [NC_000001.10:g.(155160963_155162030)]. Mutational analysis of the MUC1 VNTR region is extremely difficult due to its repetitive nature and high guanine/cytosine content (>80%) (PMIDs: 31116938, 27157321). In approximately 95% of cases the ADTKD-MUC1 pathogenic variant is the insertion of an extra cytosine within a heptanucleotide cytosine tract of a VNTR unit (PMIDs: 23396133, 29967284, 29217307). Less common is the insertion of a different nucleotide (e.g., adenine, guanine). At least 7 unique variants in the VNTR domain of MUC1, and one variant located immediately before the VNTR (PMIDs: 29156055, 29967284), have been reported in humans. MUC1 pathogenic variants result in the creation of the +1 frameshifted MUC1 protein (MUC1-fs). Expression of MUC1-fs is toxic to kidney cells and is responsible for slowly progressive chronic kidney disease, the sole manifestation of this disorder. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 600 individuals (from more than 300 families) and segregated with the disease (PMIDs: 24509297, 23946964, 29217307, 29156055, 32450155, 36250282;). MUC1 pathogenic variants causing ADTKD-MUC1 result in the creation of the same frameshifted protein (MUC1-fs). This protein accumulates within the endoplasmic reticulum Golgi intermediate compartment (ERGIC) (PMIDs: 31348885, 29967284, 36250282). In individuals with ADTKD-MUC1, MUC1-fs is found in all cell types normally expressing MUC1 (including breast, gastric mucosa, and lung) (PMID: 29967284); however, clinical manifestations of disease only occur in the kidney, where its deposition leads to accelerated apoptosis, tubular cell death, nephron dropout, and progressive chronic kidney disease. Summary of Experimental Evidence: 4 POINTS. This gene-disease association is supported by immunohistochemical studies of MUC1-fs in patient kidney biopsies, urine derived cells from patients, kidney organoids derived from ADTKD-MUC1 patients and a MUC1-fs knock-in mouse model (PMIDs: 29967284, 29217307, 31348885). In summary, MUC1 is definitively associated with autosomal dominant tubulointerstitial kidney disease due to MUC1 frameshifting mutations mainly in the VNTR (ADTKD-MUC1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP Working Group on 01/13/2021 (SOP Version 8).