Functional Null Mutations of MSRB3 Encoding Methionine Sulfoxide Reductase Are Associated with Human Deafness DFNB74

被引：84

作者：

Ahmed, Zubair M. ^{[1
,2
,3
,4
]}

Yousaf, Rizwan ^{[1
,2
,7
]}

Lee, Byung Cheon ^{[5
,6
]}

Khan, Shaheen N. ^{[7
]}

Lee, Sue ^{[8
]}

Lee, Kwanghyuk ^{[9
]}

Husnain, Tayyab ^{[7
]}

Rehman, Atteeq Ur ^{[7
,8
]}

Bonneux, Sarah ^{[10
]}

Ansar, Muhammad ^{[11
]}

Ahmad, Wasim ^{[11
]}

Leal, Suzanne M. ^{[9
]}

Gladyshev, Vadim N. ^{[5
,6
]}

Belyantseva, Inna A. ^{[8
]}

Van Camp, Guy ^{[10
]}

Riazuddin, Sheikh ^{[12
]}

Friedman, Thomas B. ^{[8
]}

Riazuddin, Saima ^{[1
,2
,3
,4
]}

机构：

[1] Cincinnati Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Mol Genet Lab, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, Dept Otolaryngol, Cincinnati, OH 45229 USA

[3] Cincinnati Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA

[4] Univ Cincinnati, Coll Med, Dept Ophthalmol, Cincinnati, OH 45229 USA

[5] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Boston, MA 02115 USA

[7] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 54500, Pakistan

[8] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA

[9] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[10] Univ Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium

[11] Quaid I Azam Univ, Fac Biol Sci, Dept Biochem, Islamabad 45320, Pakistan

[12] Univ Hlth Sci, Allama Iqbal Med Coll, Jinnah Hosp Complex, Lahore 54500, Pakistan

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2011年 / 88卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NONSYNDROMIC HEARING IMPAIRMENT; OXIDATIVE STRESS; INNER-EAR; MACULAR DEGENERATION; GAMMA-ACTIN; AGE; GENE; CELLS; APOPTOSIS; DYSTONIA;

D O I：

10.1016/j.ajhg.2010.11.010

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：19 / 29

页数：11

共 49 条

[1] PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23 [J].