Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy.
Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy.
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DOI：
10.1002/ana.24265
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发表时间：
2014-11
影响因子：
11.2
通讯作者：
Loprinzi, Charles L.
中科院分区：
文献类型：
--
作者：
Beutler, Andreas S.;Kulkarni, Amit A.;Kanwar, Rahul;Klein, Christopher J.;Therneau, Terry M.;Qin, Rui;Banck, Michaela S.;Boora, Ganesh K.;Ruddy, Kathryn J.;Wu, Yanhong;Smalley, Regenia L.;Cunningham, Julie M.;Le-Lindqwister, Nguyet Anh;Beyerlein, Peter;Schroth, Gary P.;Windebank, Anthony J.;Zuechner, Stephan;Loprinzi, Charles L.
Charcot-Marie-Tooth病（CMT）基因突变是罕见的家族性多发性神经病的病因。CMT基因的等位基因变异是否也与常见形式的多发性神经病（医学术语中被认为是“获得性”）有关尚不清楚。化疗引起的周围神经病变（CIPN）在癌症患者中很常见，并且个体不可预测。我们使用CIPN作为临床模型来研究非CMT多发神经病与CMT基因的关系。269名无神经症状的癌症患者被纳入Alliance N08C1临床试验，接受神经毒性药物紫杉醇治疗，同时进行多神经病变的前瞻性评估。通过对患者血液基因组DNA进行定向大规模平行测序，分析49个CMT基因。269例患者中有119例来自多神经病变表型分布的两端：最易患紫杉醇多神经病变和最不易患紫杉醇多神经病变的患者。发现CMT基因PRX在易患CIPN的患者中发生有害突变，而在对照组中则没有（p=8×10−3）。另一个CMT基因ARHGEF10的遗传变异与CIPN高度显著相关（p=5×10−4）。ARHGEF10信号的三个非同义语重复单核苷酸变体：rs9657362、rs2294039和rs17683288。其中，rs9657362的效果最强（比值比为4.8,p=4×10−4）。结果揭示了CMT基因等位基因变异与CIPN易感性的关联。这一发现提出了其他获得性多神经病变也可能由遗传病因共同决定的可能性，其中一些可能与已知导致CMT的表型相关孟德尔疾病的基因有关。
Mutations in Charcot-Marie-Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy—considered “acquired” in medical parlance—is unknown. Chemotherapy induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as clinical model to investigate the association of non-CMT polyneuropathy with CMT genes. 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. 49 CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood. 119 (of 269) patients were identified from the two ends of the polyneuropathy phenotype distribution: patients that were most- and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p=8×10−3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p=5×10−4). Three non-synonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio of 4.8, p=4×10−4). The results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be co-determined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
2.2
作者：
Nakamura, Tomonori;Hashiguchi, Akihiro;Takashima, Hiroshi
通讯作者：
Takashima, Hiroshi
影响因子：
50.5
作者：
Alberti, P.;Rossi, E.;Cavaletti, G.
通讯作者：
Cavaletti, G.
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
3.5
作者：
Guilbot, A;Williams, A;Claustres, M
通讯作者：
Claustres, M