A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss
A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss
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DOI：
10.1016/j.bbrc.2015.05.099
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发表时间：
2015-08-07
影响因子：
3.1
通讯作者：
Matsunaga, Tatsuo
中科院分区：
文献类型：
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作者：
Wasano, Koichiro;Mutai, Hideki;Matsunaga, Tatsuo
据报道，KCNQ 4突变可导致常染色体显性遗传性非综合征性听力损失（DFNA 2A），通常表现为儿童期轻度至中度听力损失的进行性听力损失。在这里，我们确定了一个新的KCNQ 4突变，c.1044_1051de18，在一个常染色体隐性遗传性非综合征性听力损失的家庭。先证者是突变的纯合子，出生于近亲父母;她表现出严重的听力损失，要么是先天性的，要么是儿童早期发病。先证者有一个姐妹，她是突变的杂合子，但听力正常。该突变引起移码，消除了大部分细胞质C-末端，包括A-结构域，其对蛋白质四聚体具有重要作用，以及B-片段，其是钙调蛋白（CaM）的结合位点，通过Ca离子调节通道功能。杂合子具有正常听力的事实表明，即使只有一半的蛋白质含有A结构域和B片段，也存在足够的四聚体和CaM结合位点以保持正常的表型。另一方面，纯合子中的严重听力损失表明，由于四聚体形成和CaM结合失败，蛋白质中A结构域和B片段的完全缺失导致功能丧失。该家系提示KCNQ 4基因的某些突变除了可引起常染色体显性听力损失的轻度表型外，还可引起常染色体隐性听力损失的重度表型。这种基因型/表型相关性类似于KCNQ 1中的基因型/表型相关性，KCNQ 1导致常染色体显性遗传性长QT综合征1（表型较轻）和常染色体隐性遗传性Jervell和Lange-Nielsen综合征1（表型较重），这是由于钾通道的细胞质C-末端缺失所致。(C)2015 Elsevier Inc. All rights reserved.
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_1051de18, 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. (C) 2015 Elsevier Inc. All rights reserved.