Morelli Kathryn H, Seburn Kevin L, Schroeder David G, Spaulding Emily L, Dionne Loiuse A, Cox Gregory A, Burgess Robert W
The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Cell Rep. 2017 Mar 28;18(13):3178-3191. doi: 10.1016/j.celrep.2017.03.009.
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited polyneuropathies. Mutations in 80 genetic loci can cause forms of CMT, resulting in demyelination and axonal dysfunction. The clinical presentation, including sensory deficits, distal muscle weakness, and atrophy, can vary greatly in severity and progression. Here, we used mouse models of CMT to demonstrate genetic interactions that result in a more severe neuropathy phenotype. The cell adhesion molecule Nrcam and the Na channel Scn8a (NaV1.6) are important components of nodes. Homozygous Nrcam and heterozygous Scn8a mutations synergized with both an Sh3tc2 mutation, modeling recessive demyelinating Charcot-Marie-Tooth type 4C, and mutations in Gars, modeling dominant axonal Charcot-Marie-Tooth type 2D. We conclude that genetic variants perturbing the structure and function of nodes interact with mutations affecting the cable properties of axons by thinning myelin or reducing axon diameter. Therefore, genes integral to peripheral nodes are candidate modifiers of peripheral neuropathy.
夏科-马里-图思（CMT）病是一组临床和遗传异质性的遗传性多神经病。80个基因位点的突变可导致不同类型的CMT，引起脱髓鞘和轴突功能障碍。其临床表现，包括感觉缺陷、远端肌肉无力和萎缩，在严重程度和进展方面差异很大。在此，我们利用CMT小鼠模型来证明导致更严重神经病变表型的基因相互作用。细胞粘附分子Nrcam和钠通道Scn8a（NaV1.6）是神经结的重要组成部分。纯合Nrcam和杂合Scn8a突变与Sh3tc2突变（模拟隐性脱髓鞘型夏科-马里-图思4C型）以及Gars突变（模拟显性轴突型夏科-马里-图思2D型）协同作用。我们得出结论，扰乱神经结结构和功能的基因变异与通过使髓鞘变薄或减小轴突直径而影响轴突电缆特性的突变相互作用。因此，外周神经结不可或缺的基因是周围神经病变的候选修饰基因。
