Artikel
Exome sequencing and linkage analysis identified TNC as a novel causative gene in nonsyndromic hearing loss
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Autoren
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Qiuju Wang
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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Y. Zhao
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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G. Tian
- BGI-Shenzhen, Shenzhen, China
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F. Zhao
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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L. Zong
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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D. Wang
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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L. Lan
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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Q. Li
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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B. Han
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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W. Yang
- Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Bejing, China
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H. Yang
- BGI-Shenzhen, Shenzhen, China
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J. Wang
- BGI-Shenzhen, Shenzhen, China
| Veröffentlicht: | 4. April 2012 |
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Gliederung
Text
In this study, a five-generation Chinese family with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 reported genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family with the average depth of 50-fold. Six single nucleotide variants and two indel were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 56 subjects of F013. And this missense mutation c.5317G>A (V1773M) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 101 unrelated hearing loss pedigrees found a second missense mutation, c.5368A>T, co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. These findings provide a cost effective approach to identify causal mutations in dominant hereditary diseases and reveal a novel gene TNC involved in hearing disorders.
TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin C was supposed to cause hearing loss by making nerve fibers in cochlea vulnerable for reversible injuries.
