TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of function.
TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of function.
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DOI：
10.1002/acn3.51523
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发表时间：
2022-03
影响因子：
5.3
通讯作者：
McCray BA
中科院分区：
文献类型：
--
作者：
Taga A;Peyton MA;Goretzki B;Gallagher TQ;Ritter A;Harper A;Crawford TO;Hellmich UA;Sumner CJ;McCray BA
钙渗透性离子通道TRPV 4（瞬时受体电位香草酸4）中的独特显性突变通常会导致神经肌肉或骨骼系统的非重叠疾病。然而，越来越多的证据表明，一些患者发展混合表型，包括神经肌肉和骨骼疾病的元素。我们试图确定这些患者的遗传和临床特征。我们报告了一个2岁的孩子，在TRPV4中有一个新的R616G突变，有严重的神经病变表型和双侧声带麻痹。有趣的是，在同一个残基，R616Q，不同的取代已被报道在家庭孤立的骨骼发育不良。为了深入了解混合表型的临床特征和潜在遗传决定因素，我们对先前报告的患者进行了深入分析沿着对选定的突变进行了功能和结构评估。我们描述了广泛的神经肌肉和骨骼的表现，并强调特定的突变，更频繁地与重叠综合征。我们发现，突变导致严重的，混合表型有一个较早的发病年龄，并导致更显着的细胞内钙离子升高，细胞毒性增加，并降低敏感性TRPV4拮抗作用。具有最显著的离子通道功能增益的两个突变的结构分析表明，这些突变体可能通过TRPV 4 S5跨膜结构域的破坏而引起组成性通道开放。这些发现表明，基线钙升高的程度与混合表型的发展和对药理学通道抑制的敏感性相关，这些观察结果对于TRPV 4通道病未来临床试验的设计至关重要。
Distinct dominant mutations in the calcium‐permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically cause nonoverlapping diseases of either the neuromuscular or skeletal systems. However, accumulating evidence suggests that some patients develop mixed phenotypes that include elements of both neuromuscular and skeletal disease. We sought to define the genetic and clinical features of these patients. We report a 2‐year‐old with a novel R616G mutation in TRPV4 with a severe neuropathy phenotype and bilateral vocal cord paralysis. Interestingly, a different substitution at the same residue, R616Q, has been reported in families with isolated skeletal dysplasia. To gain insight into clinical features and potential genetic determinants of mixed phenotypes, we perform in‐depth analysis of previously reported patients along with functional and structural assessment of selected mutations. We describe a wide range of neuromuscular and skeletal manifestations and highlight specific mutations that are more frequently associated with overlap syndromes. We find that mutations causing severe, mixed phenotypes have an earlier age of onset and result in more marked elevations of intracellular calcium, increased cytotoxicity, and reduced sensitivity to TRPV4 antagonism. Structural analysis of the two mutations with the most dramatic gain of ion channel function suggests that these mutants likely cause constitutive channel opening through disruption of the TRPV4 S5 transmembrane domain. These findings demonstrate that the degree of baseline calcium elevation correlates with development of mixed phenotypes and sensitivity to pharmacologic channel inhibition, observations that will be critical for the design of future clinical trials for TRPV4 channelopathies.
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影响因子：
2
作者：
Weinstein, Michael M.;Kang, Taekyu;Lachman, Ralph S.;Bamshad, Michael;Nickerson, Deborah A.;Krakow, Deborah;Cohn, Daniel H.
通讯作者：
Cohn, Daniel H.
影响因子：
3
作者：
Goyal, Navin;Skrdla, Pete;Cheriyan, Joseph
通讯作者：
Cheriyan, Joseph
影响因子：
2.2
作者：
Fiorillo, Chiara;Moro, Francesca;Bruno, Claudio
通讯作者：
Bruno, Claudio
影响因子：
9.9
作者：
Chen, D. -H.;Sul, Y.;Bird, T.
通讯作者：
Bird, T.
影响因子：
--
作者：
DELONG, R;SIDDIQUE, T
通讯作者：
SIDDIQUE, T