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.

Control of mitochondrial integrity in ageing and disease

“…MSRB2 overexpression protects human cells from H 2 O 2 -induced oxidative damage, generation of ROS, loss of mitochondrial membrane potential, protein carbonyl accumulation and apoptotic cell death, thus ensuring the mitochondrial integrity and cell survival by scavenging ROS [131]. The autosomal recessive null mutations in the human MSRB3 have been implicated in mitochondrial dysfunction leading to deafness (DFNB74 MIM:613718 [132]). …”

Methionine Sulfoxide Reductase A, B1 and B2 Are Likely to Be Involved in the Protection against Oxidative Stress in the Inner Ear

“…A previous study reported that mutations in the MSRB3 gene cause autosomal recessive hearing loss [Ahmed et al, 2011]. In addition, we recently reported that MsrB3 protein is expressed in sensory epithelia in the cochlea and vestibular tissue of the mouse, and that loss of MsrB3 in mice led to profound hearing loss due to hair cell apoptosis [Kwon et al, 2014].…”

Methionine Sulfoxide Reductase A Knockout Mice Show Progressive Hearing Loss and Sensitivity to Acoustic Trauma

“…The cochlear expressions of MsrA in the cells of the spiral ganglion, Corti cells, and the lateral wall have suggested that the presence of MsrB and MsrA in these structures can prevent cochlear damage as a result of oxidative stress [Ahmed et al, 2011;Kwon et al, 2014b]. The loss of cells in the organs of Corti, spiral ganglion, and lateral wall has been reported in hearing loss studies [Fernandez et al, 2015;Hequembourg and Liberman, 2001;Ng et al, 2015].…”

“…Studies on the roles of the Msrs on cochlear protection have been limited. Mutations of the MsrB3 gene are normally linked to autosomal recessive prelingual individual deafness; these mutations are associated with the protein-reducing capability of methionine sulfoxide [Ahmed et al, 2011]. In this experiment, the ablation of the MsrB3 in mice stimulated apoptotic death of the cells in the inner part of the ear; there was also disintegration of the stereocilia of hair cells inside the ear, and deafness was determined by 20 days of age [Kwon, et al, 2014a].…”