Légaré Cécilia, Overend Gayle, Guay Simon-Pierre, Monckton Darren G, Mathieu Jean, Gagnon Cynthia, Bouchard Luigi
Department of Biochemistry (C.L., S.-P.G., L.B.), Université de Sherbrooke, Sherbrooke; ECOGENE-21 Biocluster (C.L., S.-P.G., L.B.), Chicoutimi, Québec, Canada; Groupe de Recherche interdisciplinaire sur les maladies neuromusculaires (C.L., J.M., C.G., L.B.), Saguenay, Canada; Institute of Molecular (G.O., D.G.M.), Cell and Systems Biology, University of Glasgow, United Kingdom; and Centre de Recherche Charles-Le-Moyne-Saguenay-Lac-StJean sur les innovations en santé (J.M., C.G.), Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Canada.
Neurol Genet. 2019 May 23;5(3):e338. doi: 10.1212/NXG.0000000000000338. eCollection 2019 Jun.
To assess the effects of dystrophia myotonica protein kinase () DNA methylation (DNAme) epivariation on muscular and respiratory profiles in patients with myotonic dystrophy type 1 (DM1).
Phenotypes were assessed with standardized measures. Pyrosequencing of bisulfite-treated DNA was used to quantify DNAme levels in blood from 90 patients with DM1 (adult form). Modal CTG repeat length was assessed using small-pool PCR. The presence of Acil-sensitive variant repeats was also tested.
DNAme levels upstream of the CTG expansion (exon and intron 11) were correlated with modal CTG repeat length (r = -0.224, = 0.040; r = -0.317, = 0.003; and r = -0.241, = 0.027), whereas correlations were observed with epivariations downstream of the CTG repeats (r = 0.227; = 0.037). The presence of a variant repeat was associated with higher DNAme levels at multiple CpG sites (up to 10% higher; = 0.001). Stepwise multiple linear regression modeling showed that DNAme contributed significantly and independently to explain phenotypic variability in ankle dorsiflexor (3 CpGs: = 0.001, 0.013, and 0.001), grip ( = 0.089), and pinch ( = 0.028) strengths and in forced vital capacity (2 CpGs: = 0.002 and 0.021) and maximal inspiratory pressure ( = 0.012).
In addition to the CTG repeat length, epivariations independently explain phenotypic variability in DM1 and could thus improve prognostic accuracy for patients.
评估强直性肌营养不良蛋白激酶（）DNA甲基化（DNAme）表观变异对1型强直性肌营养不良（DM1）患者肌肉和呼吸状况的影响。
采用标准化测量方法评估表型。对亚硫酸氢盐处理后的DNA进行焦磷酸测序，以定量90例DM1患者（成人型）血液中的DNAme水平。使用小池PCR评估CTG重复序列的模式长度。还检测了对阿西尔敏感的变异重复序列的存在情况。
CTG扩增上游（外显子和第11内含子）的DNAme水平与CTG重复序列的模式长度相关（r = -0.224，= 0.040；r = -0.317，= 0.003；r = -0.241，= 0.027），而在CTG重复序列下游观察到与表观变异的相关性（r = 0.227；= 0.037）。变异重复序列的存在与多个CpG位点较高的DNAme水平相关（高达10%；= 0.001）。逐步多元线性回归模型显示，DNAme对解释踝背屈肌（3个CpG：= 0.001、0.013和0.001）、握力（= 0.089）、捏力（= 0.028）以及用力肺活量（2个CpG：= 0.002和0.021）和最大吸气压力（= 0.012）的表型变异性有显著且独立的贡献。
除了CTG重复序列长度外，表观变异独立解释了DM1的表型变异性，因此可以提高患者的预后准确性。
