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.
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.
Cheng
J
J
Institute Of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Han
D Y
DY
Dai
P
P
Sun
H J
HJ
Tao
R
R
Sun
Q
Q
Yan
D
D
Qin
W
W
Wang
H Y
HY
Ouyang
X M
XM
Yang
S Z
SZ
Cao
J Y
JY
Feng
G Y
GY
Du
L L
LL
Zhang
Y Z
YZ
Zhai
S Q
SQ
Yang
W Y
WY
Liu
X Z
XZ
He
L
L
Yuan
H J
HJ
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
D022821:RNA Splice Sites; D011960:Receptors, Estrogen; C111432:GSDME protein, human; D000094524:Gasdermins