Novel denovo TRPV4 mutation identified in a Chinese family with metatropic dysplasia inhibits chondrogenic differentiation.
Novel denovo TRPV4 mutation identified in a Chinese family with metatropic dysplasia inhibits chondrogenic differentiation.
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在一个患有变性发育不良的中国家族中发现的新的 TRPV4 突变抑制软骨形成分化。
DOI：
10.1016/j.gendis.2023.05.008
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发表时间：
2024-05
期刊：
影响因子：
6.8
通讯作者：
Zhu, Mingwei
中科院分区：
文献类型：
--
作者：
Wei, Ping;Shi, Weizhe;Nong, Tianying;Xian, Caixia;Li, Xia;Li, Zhaohui;Li, Xin;Wu, Jianping;Shang, Liyuan;Xu, Fulong;Xu, Yibo;Xu, Hongwen;Zhu, Mingwei
后退变性发育不良（MD，MIM 156530）是一种罕见的先天性骨发育不良，主要特征是严重的扁平椎体，椎体长而宽，管状骨哑铃状畸形。MD可由编码瞬时受体电位香草素家族成员4（TRPV4）的基因中的杂合突变引起。我们发现了一个新的从头突变，c。2353 T> C，在TRPV4基因中，在一个中国人轻度MD家系中。在HEK293细胞中表达突变型TRPV4导致细胞内基础Ca2+浓度升高和内质网重新分布。此外，突变体TRPV 4抑制ATDC 5细胞的软骨分化。总的来说，我们得出结论，新的突变C。该病例的致病基因为TRPV4基因2353 T> C，其致病机制可能部分与软骨细胞分化受到抑制有关。典型MD患者的临床表现为出生后身材矮小、进行性脊柱后凸、关节活动受限和外翻。此外，放射学表型主要包括椎体的扁平、椎弓根覆盖、管状骨的干骺端变宽和扇形、股骨颈缩短和腕骨骨化延迟。在轻度MD病例中，脊柱后凸并不普遍。1 TRPV4突变于2009年首次发现导致MD。2迄今为止，根据人类基因突变数据库，已发现超过50种TRPV4突变与骨骼发育不良相关。TRPV4可形成同源或异源四聚体钙离子通道，调节细胞内Ca2+浓度。3该通道的缺失或功能异常可导致多种疾病，例如骨骼发育不良和周围轴索神经病变。3
Metatropic dysplasia (MD, MIM 156530) is a rare congenital bone dysplasia primarily characterized by severe platyspondyly with long and wide vertebral bodies and dumbbell deformity of the tubular bones. MD can be caused by heterozygous mutations in the gene encoding transient receptor potential vanilloid family member 4 (TRPV4). We identified a novel de novo mutation, c. 2353 T> C, in the TRPV4 gene, in a Chinese family with mild MD. Expression of mutant TRPV4 in HEK293 cells resulted in higher basal intracellular Ca 2+ concentrations and endoplasmic reticulum redistribution. In addition, mutant TRPV4 inhibited the chondrogenic differentiation of ATDC5 cells. Overall, we concluded that the novel mutation c. 2353 T> C in the TRPV4 gene was the causative genetic lesion in this MD patient, whilst its pathogenicity might be partially attributed to the inhibition of chondrogenic differentiation.Patients diagnosed with classic MD typically present with short postnatal stature, progressive kyphoscoliosis, joint movement restriction, and genu valgum. Additionally, radiographic phenotypes primarily include platyspondyly of the vertebral bodies, overfaced vertebral pedicles, widening and scalloping metaphyses of the tubular bones, shortness of the femoral neck, and delayed ossification of the carpal bones. In mild MD cases, kyphoscoliosis is not universal. 1 TRPV4 mutations were first found to cause MD in 2009. 2 To date, over 50 mutations of TRPV4 have been found to be associated with skeletal dysplasia, according to the Human Gene Mutation Database. TRPV4 can form a homo-or heterotetramer calcium-permeable nonselective cation channel that regulates intracellular Ca 2+ concentrations. 3 The absence or abnormal functioning of this channel can cause a variety of diseases, such as skeletal dysplasia and peripheral axonal neuropathy. 3
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影响因子：
4.8
作者：
Muramatsu, Shuji;Wakabayashi, Makoto;Matsuda, Akio
通讯作者：
Matsuda, Akio
影响因子：
30.8
作者：
Rock, Matthew J.;Prenen, Jean;Cohn, Daniel H.
通讯作者：
Cohn, Daniel H.
影响因子：
9.8
作者：
Krakow, Deborah;Vriens, Joris;Cohn, Daniel H.
通讯作者：
Cohn, Daniel H.
DOI：
10.1002/ajmg.c.31335
发表时间：
2012-08-15
影响因子：
3.1
作者：
Nishimura, Gen;Lausch, Ekkehart;Unger, Sheila
通讯作者：
Unger, Sheila