A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.

Abstract

Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel.

• Authors: Koichiro Wasano, Hideki Mutai, Chie Obuchi, Sawako Masuda, Tatsuo Matsunaga
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 463 Issue 4 Pg. 582-6 (Aug 07 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26036578 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• KCNQ Potassium Channels
• KCNQ4 protein, human

Topics

• Adult
• Female
• Frameshift Mutation
• Genes, Recessive
• Hearing Loss (genetics)
• Humans
• KCNQ Potassium Channels (genetics)
• Long QT Syndrome (genetics)
• Male
• Pedigree