对周围神经病变患者进行外显子组测序揭示疾病基因

  通过进行外显子组测序，近日，来自贝勒医学院的科学家鉴别出了引发腓骨肌萎缩症（CMT）样周围神经病的基因突变；CMT是一种遗传性周围神经病，临床中该疾病主要存在两种形式，其中一种不常见的形式和一系列基因突变直接相关，包括基因CMT1A， CMTX1， RAB7和PMP22等。
  文章中，研究人员对37个无关联家庭的40名个体进行外显子组测序，其中发现17名个体都没有患周围神经病的分子原因；基于研究结果，研究者提出了三种候选疾病基因：PMP2、SPTLC3和DNAJB5，同时研究者还发现，相比对照而言，受影响的患者机体中神经病相关的基因的罕见突变率较高。
  研究者Lupski说道，我们的研究发现表明，罕见突变的组合性效应或许会引发患者疾病负担及变异性的增加；在40名病人中，研究者发现有6名患者机体中都存在引发疾病的等位基因，包括基因MFN2、MED25及ABHD12的突变等，同时研究者还在已知的神经病相关基因中发现了一种新型的等位基因。
  随后研究热人员进行了基于斑马鱼的功能性实验，研究者成功地抑制了多种神经病相关的基因，而这些基因一旦两两联合作用就会增加疾病的严重性；最后研究者表示，基因突变的负担或许会影响到疾病表型，进而引发疾病的临床异质性及疾病的严重程度。研究者希望后期可以通过更多研究来揭示出更多引发周围神经病变的基因，这或许为后期开发新型疗法来治疗疾病提供新的思路和希望。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
Cell Reports    10.1016/j.celrep.2015.07.023
Claudia Gonzaga-Jauregui21, Tamar Harel21, Tomasz Gambin, Maria Kousi, Laurie B. Griffin, Ludmila Francescatto, Burcak Ozes, Ender Karaca, Shalini N. Jhangiani, Matthew N. Bainbridge, Kim S. Lawson, Davut Pehlivan, Yuji Okamoto, Marjorie Withers, Pedro Mancias, Anne Slavotinek, Pamela J. Reitnauer, Meryem T. Goksungur, Michael Shy, Thomas O. Crawford, Michel Koenig, Jason Willer, Brittany N. Flores, Igor Pediaditrakis, Onder Us, Wojciech Wiszniewski, Yesim Parman, Anthony Antonellis, Donna M. Muzny, Baylor-Hopkins Center for Mendelian Genomics, Nicholas Katsanis, Esra Battaloglu, Eric Boerwinkle, Richard A. Gibbs, James R. Lupski.
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.