TRPV4-associated skeletal dysplasias
TRPV4-associated skeletal dysplasias
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DOI：
10.1002/ajmg.c.31335
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发表时间：
2012-08-15
影响因子：
3.1
通讯作者：
Unger, Sheila
中科院分区：
文献类型：
--
作者：
Nishimura, Gen;Lausch, Ekkehart;Unger, Sheila
TRPV 4基因的显性突变导致骨发育不良家族，并形成连续的表型谱，包括（严重程度递减）致死性和非致死性后向性发育不良（MD）、脊椎骨发育不良Kozlowski型（SMDK）和常染色体显性短肢畸形。几种罕见的变异表型，有一些重叠，但在某些方面偏离一般模式也已被描述。已知的变异表型为Maroteaux型脊椎骨骺发育不良（假性Morquio 2型）、旁肌发育不良和家族性短指关节病。有趣的是，不同的TRPV 4突变与显性遗传性神经系统疾病有关，如先天性脊髓性肌萎缩症和遗传性运动和感觉神经病。最后，已经确定了少数患者的TRPV 4突变导致骨骼发育不良与周围神经病变相结合的表型。TRPV 4基因编码一种参与多种不同细胞过程的调节钙通道。已经报道了超过50种不同的TRPV 4突变，其中两个密码子似乎是突变热点：外显子15中的P799，主要与MD相关，外显子11中的R594，与SMDK相关。虽然迄今为止测试的大多数致病性突变导致体外钙通道激活，但TRPV 4激活导致骨骼发育不良和/或周围神经病变的机制仍不清楚，这组疾病中的基因型-表型相关性仍有些神秘。由于大多数突变的表型表达似乎是相对恒定的，因此仔细的临床和放射学评估在指导分子分析中是有用的。(C)2012 Wiley Periodicals，Inc.
Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotypephenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis. (C) 2012 Wiley Periodicals, Inc.