title: Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74.
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.
authors.affiliation: Laboratory of Molecular Genetics, Division of Pediatric Otolaryngology Head & Neck Surgery, Cincinnati Children's Hospital Research Foundation, and the Department of Otolaryngology, College of Medicine, University of Cincinnati, OH, 45229 USA.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Rizwan
authors.initials: R
authors.lastname: Yousaf
authors.forename: Byung Cheon
authors.initials: BC
authors.lastname: Lee
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Sue
authors.initials: S
authors.lastname: Lee
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Tayyab
authors.initials: T
authors.lastname: Husnain
authors.forename: Atteeq Ur
authors.initials: AU
authors.lastname: Rehman
authors.forename: Sarah
authors.initials: S
authors.lastname: Bonneux
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.forename: Inna A
authors.initials: IA
authors.lastname: Belyantseva
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
mesh_terms: D000368:Aged; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D003638:Deafness / Q000201:enzymology* / Q000235:genetics*; D007758:Ear, Inner / Q000201:enzymology; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D056426:Genetic Loci; D034381:Hearing Loss / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D051150:Methionine Sulfoxide Reductases; D051379:Mice; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C017800:zinc-binding protein; D050862:Oxidoreductases Acting on Sulfur Group Donors; D051150:Methionine Sulfoxide Reductases; C524352:MSRB3 protein, human