Abstract
The DFNB74 locus for autosomal-recessive, nonsyndromic deafness segregating in three families was previously mapped to a 5.36 Mb interval on chromosome 12q14.2-q15. Subsequently, we ascertained five additional consanguineous families in which deafness segregated with markers at this locus and refined the critical interval to 2.31 Mb. We then sequenced the protein-coding exons of 18 genes in this interval. The affected individuals of six apparently unrelated families were homozygous for the same transversion (c.265T>G) in MSRB3, which encodes a zinc-containing methionine sulfoxide reductase B3. c.265T>G results in a substitution of glycine for cysteine (p.Cys89Gly), and this substitution cosegregates with deafness in the six DFNB74 families. This cysteine residue of MSRB3 is conserved in orthologs from yeast to humans and is involved in binding structural zinc. In vitro, p.Cys89Gly abolished zinc binding and MSRB3 enzymatic activity, indicating that p.Cys89Gly is a loss-of-function allele. The affected individuals in two other families were homozygous for a transition mutation (c.55T>C), which results in a nonsense mutation (p.Arg19X) in alternatively spliced exon 3, encoding a mitochondrial localization signal. This finding suggests that DFNB74 deafness is due to a mitochondrial dysfunction. In a cohort of 1,040 individuals (aged 53-67 years) of European ancestry, we found no association between 17 tagSNPs for MSRB3 and age-related hearing loss. Mouse Msrb3 is expressed widely. In the inner ear, it is found in the sensory epithelium of the organ of Corti and vestibular end organs as well as in cells of the spiral ganglion. Taken together, MSRB3-catalyzed reduction of methionine sulfoxides to methionine is essential for hearing.
| Original language | English |
|---|---|
| Pages (from-to) | 19-29 |
| Number of pages | 11 |
| Journal | American Journal of Human Genetics |
| Volume | 88 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2011 Jan 7 |
| Externally published | Yes |
Bibliographical note
Funding Information:We wish to thank all participants in this study. We thank Shannon Bell for technical assistance and Dennis Drayna and Karen Friderici for critiques of the manuscript. This work was supported by Cincinnati Children's Hospital Research Foundation (CCHMC) intramural research funds to SR and ZA, the National Institute on Deafness and Other Communication Disorders, National Institutes of Health (NIDCD/NIH) research grant R00-DC009287-03, a Career Development Award from Research to Prevent Blindness (to Z.A.), and National Institute on Aging, NIH grant AG021518 (to V.N.G.). S. B. is a fellow of the Research Foundation Flanders (FWO-Vlaanderen). Work in Pakistan was supported by the Higher Education Commission to S.R. (Lahore); funding from World Health Organization Regional Office for the Eastern Mediterranean (EMRO) and COMSTECH (Organization of the Islamic Conference [OIC] Standing Committee on Scientific and Technological Cooperation) and from the Ministry of Science and Technology (MoST) to S.R. (Lahore); the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 contract no. 08/009 to S.R. (Islamabad). Part of the work was funded by the Higher Education Commission (HEC), Government of Pakistan, and the NIH National Institute of Deafness and other Communication Disorders grant DC03594 to S.M.L. Genotyping services were partially provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number N01-HG-65403. Work at NIDCD/NIH was supported by intramural funds DC00039-14 to T.B.F.
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)