This article is a US Government work and, as such, is in the public domain in the United States of America.
Article first published online: 7 JAN 2008
This article is a US Government work and, as such, is in the public domain in the United States of America. Published in 2008 by Wiley-Liss, Inc.
Special Issue: Focus on Pharmacogenetics
Volume 29, Issue 4, pages 502–511, April 2008
How to Cite
Riazuddin, S., Nazli, S., Ahmed, Z. M., Yang, Y., Zulfiqar, F., Shaikh, R. S., Zafar, A. U., Khan, S. N., Sabar, F., Javid, F. T., Wilcox, E. R., Tsilou, E., Boger, E. T., Sellers, J. R., Belyantseva, I. A., Riazuddin, S. and Friedman, T. B. (2008), Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. Hum. Mutat., 29: 502–511. doi: 10.1002/humu.20677
Communicated by Dvorah Abeliovich
- Issue published online: 10 MAR 2008
- Article first published online: 7 JAN 2008
- Manuscript Accepted: 7 OCT 2007
- Manuscript Received: 25 JUN 2007
- Higher Education Commission, Ministry of Science and Technology in Islamabad, Pakistan
- National Institute on Deafness and Other Communication Disorders (NIDCD). Grant Numbers: ZO1 DC000035-07, ZO1 DC000039-07
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. Grant Number: CRP/PAK02-01 (Contract no 02/013)
- nonsyndromic hearing loss;
- Usher syndrome;
- hair cell;
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.