2002 Fiscal Year Final Research Report Summary
Identification of causative gene for hereditary low-frequency sensorineural hearing loss
| Project/Area Number |
13671787
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Nagasaki University |
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Principal Investigator |
SAKIHAMA Noriyuki University Hospital, Assistant Professor, 医学部附属病院, 講師 (60264230)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Naomichi Shool of Medicine, Associate Professor, 医学部, 助教授 (80325638)
YOSHIURA Koh-ichiro School of Medicine, Assistant Professor, 医学部, 助手 (00304931)
KIKUCHI Toshihiko Tohoku University Hospital, Assistant Professor, 医学部附属病院, 講師 (70177799)
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| Project Period (FY) |
2001 – 2002
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| Keywords | hereditary hearing loss / low frequency sensorineural hearing loss / WFS1 gene / linkage analysis / positional candidate gene approach |
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| Research Abstract |
We encoutered 10 Japanese families with nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) in Nagasaki. Following informed consent, a family with 30 members joined a clinical evaluation study and genetic analyses. Clinical manifestations revealed that their, LFSNHL was consistent with DFNA6/14-type hearing impairment, although they never had any tinnitus. An LFSNHL locus was assigned to chromosome 4pl6. We performed a genome-wide linkage analysis of the family in which 20 members were affected with LFSNHL using highly polymorphic microsatellite markers. We obtained a maximum LOD score of 5.36 at a recombination fraction of 0.05 (P=1.00) at the D4S2983 locus on 4p16. Haplotype analysis revealed that the disease locus mapped to between D4S2366 and D4S2983. Mutations in WES1 have been found to cause LFSNHL in families with DFNA6 and DFNA14. We analysed nine genes in the candidate region (FLJ11230, HMGE, KIAA0232, KIAA0935, KIAA1322, LOC93623, LOC114923, PGR1, and S100P) and WFS1. Mutation analysis revealed a novel missense mutation (K634T) in WFS1. We thus concluded that the LFSNHL in this family was caused by the WFS1 mutation. The mutation observed (K634T) was located in the hydrophobic, extracytoplasmic, juxta-transmembrane region of the WFS1 protein, wolframin. This unique mutation site in our patients is likely related to their milder phenotype (lacking tinnitus) compared with those of six previous DFNA6/14 patients with mutations. It is likely that a genotype-phenotype correlation is also applicable in the case of DFNA6/14.
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