Department of Medicine, University College London, UK.
Nat Genet. 2010 Feb;42(2):170-4. doi: 10.1038/ng.512. Epub 2009 Dec 27.
Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant neuropathy characterized by limb, diaphragm and laryngeal muscle weakness. Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.11. We sequenced all genes in this region and identified two heterozygous missense mutations in the TRPV4 gene, C805T and G806A, resulting in the amino acid substitutions R269C and R269H. TRPV4 is a well-known member of the TRP superfamily of cation channels. In TRPV4-transfected cells, the CMT2C mutations caused marked cellular toxicity and increased constitutive and activated channel currents. Mutations in TRPV4 were previously associated with skeletal dysplasias. Our findings indicate that TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. The CMT2C-associated mutations lie in a distinct region of the TRPV4 ankyrin repeats, suggesting that this phenotypic variability may be due to differential effects on regulatory protein-protein interactions.
腓骨肌萎缩症 2C 型（CMT2C）是一种常染色体显性遗传性周围神经病，其特征是肢体、膈肌和喉肌无力。两个不相关的 CMT2C 家系与染色体 12q24.11 存在显著连锁。我们对该区域的所有基因进行了测序，在 TRPV4 基因中发现了两个杂合错义突变 C805T 和 G806A，导致氨基酸取代 R269C 和 R269H。TRPV4 是 TRP 阳离子通道超家族的知名成员。在 TRPV4 转染细胞中，CMT2C 突变导致明显的细胞毒性和增加的组成型和激活的通道电流。TRPV4 突变先前与骨骼发育不良有关。我们的研究结果表明，TRPV4 突变也可引起周围神经的退行性疾病。与 CMT2C 相关的突变位于 TRPV4 锚蛋白重复的一个独特区域，表明这种表型变异性可能是由于对调节蛋白-蛋白相互作用的不同影响所致。
