TRPV4 mutations in children with congenital distal spinal muscular atrophy
TRPV4 mutations in children with congenital distal spinal muscular atrophy
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DOI：
10.1007/s10048-012-0328-7
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发表时间：
2012-08-01
期刊：
影响因子：
2.2
通讯作者：
Bruno, Claudio
中科院分区：
文献类型：
--
作者：
Fiorillo, Chiara;Moro, Francesca;Bruno, Claudio
以运动神经元丢失和肌肉无力为特征的遗传性疾病在遗传上是异质性的。最近在远端脊髓性肌萎缩症(DSMA)中发现了编码瞬时受体潜在香草素4(TRPV4)的基因突变，这促使我们在一小部分表型相容的儿童中筛查TRPV4突变。在一名患有DSMA并声带瘫痪的女孩中，我们发现了一种新的变异体(p.P97R)，它位于TRPV4蛋白的胞浆N端，位于ankyrin-Repeat结构域的上游，那里是绝大多数与疾病相关的突变的所在地。在另一名患有先天性骨质疏松症的儿童中，我们检测到了一个先前报道的突变(p.R232C)。对新的p.P97R突变在异源系统中的功能分析表明了一种功能丧失的机制。两名患者的肌肉、皮肤和培养的皮肤成纤维细胞中的蛋白质定位研究显示，蛋白质表达正常。4例未累及骨骼或声带的儿童未检测到TRPV4基因突变。除了TRPV4相关疾病的临床和分子异质性外，我们的结果还表明，对伴有骨骼异常和声带瘫痪的先天性DSMA患者进行TRPV4基因的分子检测是必要的。
Inherited disorders characterized by motor neuron loss and muscle weakness are genetically heterogeneous. The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA) prompted us to screen for TRPV4 mutations in a small group of children with compatible phenotype. In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R) localized in the cytosolic N-terminus of the TRPV4 protein, upstream of the ankyrin-repeat domain, where the great majority of disease-associated mutations reside. In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C). Functional analysis of the novel p.P97R mutation in a heterologous system demonstrated a loss-of-function mechanism. Protein localization studies in muscle, skin, and cultured skin fibroblasts from both patients showed normal protein expression. No TRPV4 mutations were detected in four children with dSMA without bone or vocal cord involvement. Adding to the clinical and molecular heterogeneity of TRPV4-associated diseases, our results suggest that molecular testing of the TRPV4 gene is warranted in cases of congenital dSMA with bone abnormalities and vocal cord paralysis.