Mutations in the Gene Encoding the Calcium-Permeable Ion Channel TRPV4 Produce Spondylometaphyseal Dysplasia, Kozlowski Type and Metatropic Dysplasia
Mutations in the Gene Encoding the Calcium-Permeable Ion Channel TRPV4 Produce Spondylometaphyseal Dysplasia, Kozlowski Type and Metatropic Dysplasia
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DOI：
10.1016/j.ajhg.2009.01.021
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发表时间：
2009-03-13
影响因子：
9.8
通讯作者：
Cohn, Daniel H.
中科院分区：
文献类型：
--
作者：
Krakow, Deborah;Vriens, Joris;Cohn, Daniel H.
腰椎滑脱症是一组以椎体和管状骨干骺端异常为特征的矮小型疾病。SMD Kozlowski型（SMDK）是一种定义明确的常染色体显性SMD，其特征是显著的脊柱侧凸和骨盆轻度干骺端异常。椎骨表现出类似于常染色体显性短肢症的扁平椎弓根和覆盖椎弓根，这可能是由于编码TRPV 4（一种钙渗透性离子通道）的基因中激活突变的杂合性所致。6例SMDK患者中有6例的突变分析显示TRPV4错义突变为杂合性，其中1例预测R594 H置换的突变在4例患者中复发。类似于常染色体显性短肢症，突变改变了体外基础钙通道活性。间变性发育不良是另一种SMD，已提出具有临床和遗传异质性。非致死性后向生长发育不良的患者表现为进行性脊柱侧凸，广泛的干骺端受累的肩胛骨和腕骨骨化延迟。由于SMDK和转移性发育不良之间的一些相似的放射学特征，FRPV4被测试为非致死性转移性发育不良的疾病基因。在两个散发的情况下，杂合性的从头错义突变TRPV4被发现。研究结果表明，TRPV4突变产生的表型谱的骨骼发育不良，从轻度常染色体显性短肢畸形SMDK常染色体显性异向性发育不良，这表明这些疾病应被归类为一个新的骨发育不良家族。
The spondylometaphyseal dysplasias (SMDs) are a group of short-stature disorders distinguished by abnormalities in the ver-tebrae and the metaphyses of the tubular bones. SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles similar to autosomal-dominant brachyolmia, which can result from heterozygosity for activating mutations in the gene encoding TRPV4, a calcium-permeable Ion channel. Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. Metatropic dysplasia is another SMD that has been proposed to have both clinical and genetic heterogeneity. Patients with the nonlethal form of metatropic dysplasia present with a progressive scoliosis, widespread metaphyseal involvement of the appendicular skeleton, and carpal ossification delay. Because of some similar radiographic features between SMDK and metatropic dysplasia, 'FRPV4 was tested as a disease gene for nonlethal metatropic dysplasia. In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family.