Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family
Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family
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DOI：
10.1136/jmg.2009.075358
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发表时间：
2010-10-01
影响因子：
4
通讯作者：
Ikegawa, S.
中科院分区：
文献类型：
--
作者：
Dai, J.;Kim, O-H;Ikegawa, S.
背景TRPV4是一种编码钙离子通透性非选择性阳离子通道的基因，最近在一系列骨骼发育不良症中发现了突变，这些骨骼发育不良包括短暂性骨质疏松症、脊柱干骺端发育不良、Kozlowski型(SMDK)和化生性发育不良(MD)。然而，总共只检测到7个错义突变。目的和方法通过对22例MD和20例SMDK患者的基因组DNA进行聚合酶链式反应-直接测序，检测TRPV4突变谱和表型-基因相关性。总共在41名受试者中鉴定出19个不同的杂合子突变；两个是复发性的，17个是新的。在MD中，在9名受试者中发现了一个复发的P799L突变，并发现了10个新的突变，包括TRPV4的第一个缺失突变F471del。在SMDK中，在12名受试者中发现了一个重复的R594H突变，并发现了7个新的突变。还观察到突变的位置与疾病表型之间的关联。因此，外显子15上的P799是MD突变的热点密码子，该密码子存在4种不同的氨基酸替换，而外显子11上的R594是SMDK突变的热点。结论本研究提供了MD和SMDK的TRPV4突变谱，显示了该基因上非随机分布突变的基因型-表型相关性和潜在的功能意义。这些结果将有助于诊断实验室建立有效的筛查策略，用于TRPV4异常增殖症家族疾病的基因诊断。
Background Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear.Objectives and methods To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands.Results TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations.Conclusion The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.