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Nephrol Dial Transplant. 2017 Dec 1;32(12):2010-2017. doi: 10.1093/ndt/gfx083.

Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein.

Author information

1
Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
2
Department of Advanced Technology of Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.
3
Laboratory of Reproductive Engineering, Institute of Experimental Animal Sciences, Osaka University Graduate School of Medicine, Osaka, Japan.
4
Department of Genome Informatics, Osaka University Graduate School of Medicine, Osaka, Japan.
5
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
6
Medical Solutions Division, NEC Corporation, Tokyo, Japan.
7
Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
8
Department of Biomedical Ethics and Public Policy, Osaka University Graduate School of Medicine, Osaka, Japan.

Abstract

Background:

Medullary cystic kidney disease Type 1 is an autosomal dominant tubulointerstitial kidney disease (ADTKD). Recently, mucin 1 (MUC1) was identified as a causal gene of medullary cystic kidney disease (ADTKD-MUC1). However, the MUC1 mutation was found to be a single cytosine insertion in a single copy of the GC-rich variable number of tandem repeats (VNTRs), which are very difficult to analyze by next-generation sequencing. To date, other mutations have not been detected in ADTKD-MUC1, and the mutant MUC1 protein has not been analyzed because of the difficulty of genetically modifying the VNTR sequence.

Methods:

We conducted whole-exome analyses of an ADTKD family by next-generation sequencing. We also performed histopathological analyses of a renal biopsy from a pedigree family member. We constructed a mutant protein expression vector based on the patient genome sequence and characterized the nature of the mutant protein.

Results:

We found a novel frameshift mutation before the VNTR in the MUC1 gene. The resulting mutant MUC1 protein had a very similar amino acid sequence and predicted 3D structure to the previously reported mutant protein. Notably, the recombinant mutant MUC1 protein was trapped in the cytoplasm and appeared to self-aggregate. The patient native mutant protein was also found in urine exosomes.

Conclusions:

This novel frameshift mutation in the MUC1 gene and consequent mutant protein may contribute to the future discovery of the pathophysiology of ADTKD-MUC1. The mutant MUC1 protein in urine exosomes may be used for non-DNA-related diagnosis.

KEYWORDS:

ADTKD; ADTKD-MUC1; MUC1; VNTR; frameshift mutation

PMID:
29156055
DOI:
10.1093/ndt/gfx083
[Indexed for MEDLINE]

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