Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss

被引:178
|
作者
Bespalova, IN
Van Camp, G
Bom, SJH
Brown, DJ
Cryns, K
DeWan, AT
Erson, AE
Flothmann, K
Kunst, HPM
Kurnool, P
Sivakumaran, TA
Cremers, CWRJ
Leal, SM
Burmeister, M
Lesperance, MM
机构
[1] Univ Michigan, Dept Otolaryngol Head & Neck Surg, Div Pediat Otolaryngol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Mental Hlth Res Inst, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA
[5] Univ Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium
[6] Univ Nijmegen, Dept Otorhinolaryngol, NL-6500 HB Nijmegen, Netherlands
[7] Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA
关键词
D O I
10.1093/hmg/10.22.2501
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.
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收藏
页码:2501 / 2508
页数:8
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