title: A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family.
abstract: We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.
authors.affiliation: Institute Of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.forename: D Y
authors.initials: DY
authors.lastname: Han
authors.forename: P
authors.initials: P
authors.lastname: Dai
authors.forename: H J
authors.initials: HJ
authors.lastname: Sun
authors.forename: R
authors.initials: R
authors.lastname: Tao
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.forename: D
authors.initials: D
authors.lastname: Yan
authors.forename: W
authors.initials: W
authors.lastname: Qin
authors.forename: H Y
authors.initials: HY
authors.lastname: Wang
authors.forename: X M
authors.initials: XM
authors.lastname: Ouyang
authors.forename: S Z
authors.initials: SZ
authors.lastname: Yang
authors.forename: J Y
authors.initials: JY
authors.lastname: Cao
authors.forename: G Y
authors.initials: GY
authors.lastname: Feng
authors.forename: L L
authors.initials: LL
authors.lastname: Du
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Zhang
authors.forename: S Q
authors.initials: SQ
authors.lastname: Zhai
authors.forename: W Y
authors.initials: WY
authors.lastname: Yang
authors.forename: X Z
authors.initials: XZ
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: H J
authors.initials: HJ
authors.lastname: Yuan
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D002681:China; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D008040:Genetic Linkage; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D000094524:Gasdermins
chemical_list: D022821:RNA Splice Sites; D011960:Receptors, Estrogen; C111432:GSDME protein, human; D000094524:Gasdermins