Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein.
Nephrol Dial Transplant
; 32(12): 2010-2017, 2017 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-29156055
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mutação da Fase de Leitura
/
Rim Policístico Autossômico Dominante
/
Mucina-1
/
Proteínas Mutantes
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article