Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy.
Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy.
复制标题
中国先天性肌营养不良症患者体内两种新型 LAMA2 突变的鉴定
DOI：
10.3389/fgene.2018.00043
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发表时间：
2018
影响因子：
3.7
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Zhou J;Tan J;Ma D;Zhang J;Cheng J;Luo C;Liu G;Wang Y;Xu Z
由层粘连蛋白α2亚单位(LAMA2)突变引起的MDC1A型肌营养不良症是先天性肌营养不良症(CMD)的主要亚型。在此，我们描述了一位患有MDC1a的中国患者，他在出生后17天因消瘦和喂养困难而入院。通过靶向捕获和下一代测序(NGS)鉴定突变，并通过桑格测序进一步确认。通过短串联重复序列分析确认亲子关系。体格检查显示营养不良、吸力差、阑尾低张。2月龄时血清CK水平为2483U/L，4月龄时为1962U/100U。1个月龄时，头颅磁共振表现为T2加权像高信号，顶叶和枕叶T1加权像高信号，液体衰减反转恢复像(FLAIR)弥散加权像(DWI)和低信号，小脑和蛛网体正常。在7个月大的时候，观察到发育里程碑延迟，她无法翻身和抬起头。靶向捕获和NGS检测到LAMA2基因的一个点突变(c.1782+2T>；G)和一个移码重复(c.8217dupT)，并经Sanger测序进一步证实。此外，多个短串联重复序列标记的基因分型证实了父子关系，证明该点突变是从头开始的。这个移码重复(c.8217dupT)是从她的母亲那里遗传来的，预计会导致第2740个氨基酸残基上Pro(P)替换为Ser(S)，并产生过早截断的蛋白质。计算机分析表明，突变(C.1782+2T>；G)可能导致LAMA2的异常剪接。我们的病例进一步证实了MDC1A的临床异质性，并提出了两个新的LAMA2突变以扩大MDC1A的突变谱。
Merosin-deficient CMD type 1A (MDC1A), caused by mutations of laminin subunit alpha 2 (LAMA2), is a predominant subtype of congenital muscular dystrophy (CMD). Herein, we described a Chinese patient with MDC1A who was admitted to hospital 17 days after birth because of marasmus and feeding difficulties. Mutations were identified by targeted capture and next generation sequencing (NGS) and further confirmed by Sanger sequencing. Paternity was confirmed by short tandem repeat analysis. Physical examination showed malnutrition, poor suck and appendicular hypotonia. Her serum CK levels were 2483 and 1962 U/L at 2 and 4 months of age, respectively. Brain magnetic resonance imaging performed at 1 month of age presented hyperintensity on T2-weighted images, T1-weighted images in parietal and occipital lobes, and diffusion-weighted image (DWI) as well as hypointensity on fluid attenuated inversion recovery (FLAIR) image; however, the cerebellum and corpus arenaceum were normal. At 7 months of age, delayed developmental milestones were observed, and she failed to turn her body over and raise her head up. A point mutation (c.1782+2T > G) and a frameshift duplication (c.8217dupT) in the LAMA2 gene were identified by targeted capture and NGS and further confirmed by Sanger sequencing. Moreover, genotyping with multiple short tandem repeat markers confirmed paternity to demonstrate that the point mutation is de novo. The frameshift duplication (c.8217dupT), inherited from her mother, was predicted to cause a substitution of Pro (P) to Ser (S) at the 2740th amino-acid residue and generate a prematurely truncated protein. The in silico analysis suggests that the mutation (c.1782+2T > G) may lead to aberrant splicing of LAMA2. Our case further confirms the heterogeneous clinical spectrum of MDC1A and presents two novel LAMA2 mutations to expand the mutation spectrum of MDC1A.