A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation.
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.
Kamada
Fumiaki
F
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.|21st COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation", Tohoku University, Sendai, Japan.
Kure
Shigeo
S
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. skure@mail.tains.tohoku.ac.jp.|21st COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation", Tohoku University, Sendai, Japan. skure@mail.tains.tohoku.ac.jp.
Kudo
Takayuki
T
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Suzuki
Yoichi
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Oshima
Takeshi
T
Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japan.
Ichinohe
Akiko
A
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Kojima
Kanako
K
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Niihori
Tetsuya
T
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Kanno
Junko
J
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Narumi
Yoko
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Narisawa
Ayumi
A
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Kato
Kumi
K
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.|21st COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation", Tohoku University, Sendai, Japan.
Aoki
Yoko
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.|21st COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation", Tohoku University, Sendai, Japan.
Ikeda
Katsuhisa
K
Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japan.
Kobayashi
Toshimitsu
T
Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japan.
Matsubara
Yoichi
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.|21st COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation", Tohoku University, Sendai, Japan.
D044466:Asian People; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005838:Genotype; D006316:Hearing Loss, High-Frequency / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion
D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human