Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans

Abstract

BackgroundOne of the causes of sensorineural hearing loss (SNHL) is degeneration of the inner hair cells in the organ of Corti in the cochlea. The SLC17A8 (solute carrier family 17, member 8) gene encodes vesicular glutamate transporter 3 (VGLUT3), and among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair cells (IHCs). VGLUT3 transports the neurotransmitter glutamate into the synaptic vesicles of the IHCs. Mutation of the SLC17A8 gene is reported to be associated with DFNA25 (deafness, autosomal dominant 25), an autosomal dominant non-syndromic hearing loss (ADNSHL) in humans.MethodsIn this study, we performed a genetic analysis of 87 unrelated Korean patients with ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean population.ResultsWe found a novel heterozygous frameshift mutation, 2 non-synonymous variations, and a synonymous variation. The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to asparagine at amino acid position 206, resulted in a termination codon at amino acid position 209. This alteration is predicted to encode a truncated protein lacking transmembrane domains 5 to 12. This mutation is located in a highly conserved region in VGLUT3 across multiple amino acid alignments in different vertebrate species, but it was not detected in 100 unrelated controls who had normal hearing ability. The results from our study suggest that the p.M206Nfs*4 mutation in the SLC17A8 gene is likely a pathogenic mutation that causes ADNSHL.ConclusionOur findings can facilitate the prediction of the primary cause of ADNSHL in Korean patients.

A novel unbiased test for molecular convergent evolution and discoveries in echolocating, aquatic and high-altitude mammals

“…For example, the 18 genes we flag in the context of echolocation, have all been observed to cause cochlear ganglion degeneration when mutated. As expected, several of these genes have also been implicated in human hearing loss 30,31 . A nice amino acid level example of "right" and "wrong" mutations (in the right context, at the right time) is the convergent bat & whale F115Y mutation in GJB2, found at the center of three codons, each of which is known to independently cause hearing loss in humans when mutated 32 (Fig.…”

VGLUT3-p.A211V variant fuses stereocilia bundle and elongates synaptic ribbons in the human deafness DFNA25

“…Only few mutations that cause progressive and early-onset form of human deafness DFNA25 have been described (Ryu et al, 2016;Ruel et al, 2008). Among them, the c.616dupA…”

“…variant of SLC17A8 introduces a stop codon and hence leads to a truncated protein (Ryu et al, 2016). Another variant is the pA211V allele of SLC17A8 (Ruel et al, 2008).…”

“…Mutations in the SLC17A8 gene are associated with DFNA25, an autosomal-dominant and progressive form of human deafness (Ruel et al, 2008;Ryu et al, 2016). SLC17A8 encodes the vesicular glutamate transporter type 3 (VGLUT3) which belongs to the VGLUTs family responsible for glutamate loading into the synaptic vesicles, a critical step to achieve synaptic transfer (Gras et al, 2002;Fremeau et al, 2002;Takamori et al, 2002).…”

Hair Cell Afferent Synapses: Function and Dysfunction

“…However, the afferent boutons of the primary auditory fibers projecting to Vglut3 −/− IHCs do not have synaptic-evoked glutamate receptor currents, indicating a failure of presynaptic glutamate release. In humans, the p.A211V and p.M206Nfs à 4 mutations of the gene encoding VGLUT3 (Slc17a8) are responsible for a progressive hearing loss (DFNA25 [Ruel et al 2008;Ryu et al 2016]), linking an auditory synaptopathy to the VGLUT3 defect.…”