Abstract
Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype–phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.
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Acknowledgements
We are grateful to the family members for participating in this study. We thank Ms. Ikuko Sato and Ms. Yasuko Murayama for excellent technical assistance. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and grants from the Ministry of Health, Labor, and Welfare, Japan.
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Kamada, F., Kure, S., Kudo, T. et al. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype–phenotype correlation. J Hum Genet 51, 455–460 (2006). https://doi.org/10.1007/s10038-006-0384-7
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DOI: https://doi.org/10.1007/s10038-006-0384-7
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