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Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function
Author(s) -
Riazuddin Saima,
Nazli Sabiha,
Ahmed Zubair M.,
Yang Yi,
Zulfiqar Fareeha,
Shaikh Rehan S.,
Zafar Ahmed U.,
Khan Shaheen N.,
Sabar Farooq,
Javid Fouzia T.,
Wilcox Edward R.,
Tsilou Ekaterini,
Boger Erich T.,
Sellers James R.,
Belyantseva Inna A.,
Riazuddin Sheikh,
Friedman Thomas B.
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20677
Subject(s) - biology , usher syndrome , genetics , allele , nonsense mutation , mutant , exon , phenotype , microbiology and biotechnology , gene , missense mutation , retinitis pigmentosa
Recessive mutations of MYO7A , encoding unconventional myosin VIIA, can cause either a deaf‐blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafness segregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2 / USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygous mutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due to a novel three‐nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. We hypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question we investigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNA expression constructs containing engineered mutations of mouse Myo7a at codons equivalent to pathogenic USH1B and DFNB2 alleles of human MYO7A . We show that in transfected mouse hair cells an USH1B mutant GFP‐myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP‐myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype (DFNB2) than the USH1B ‐associated alleles because the resulting protein retains some degree of normal function. Hum Mutat 29(4), 502–511, 2008. Published 2008 Wiley‐Liss, Inc.