1例肢带型肌营养不良1B型的临床和遗传学特点

本文报道1例LMNA基因新发剪接杂合突变所致的肢带型肌营养不良1B型（LGMD1B）。患儿表现为进行性加重的行走乏力，肩胛带肌和下肢近端肌肉无萎缩，四肢肌张力正常，上肢肌力4级、下肢肌力4级，Gower征（+）；CK 779 U/L；肌肉病理HE染色提示肌营养不良表现，免疫组化显示Lamin A蛋白表达无明显减少；二代基因测序显示患儿LMNA基因存在新发的c.810+2T > C剪接位点杂合突变，其父母LMNA基因该位点正常。GERP++RS软件预测该突变位点具有高度保守性；Human Splice Finder和Spliceman软件预测该突变可能为致病性突变；ExPASy预测新的剪接变体氨基酸序列变短。转录组测序提示患者肌肉的mRNA存在两种序列：一种为正常序列，占92.2%；另一种为部分4号内含子保留，占7.8%，即异常剪接变体。LGMD1B是由位于常染色体1q22的LMNA基因突变所致的常染色体显性遗传性肌病，本研究的发现扩展了LMNA基因突变谱，为LGMD1B诊断提供了帮助。

Clinical and genetic features of limb-girdle muscular dystrophy type 1B: a case report

This article reports a case of limb-girdle muscular dystrophy type 1B (LGMD1B) caused by a novel splicing heterozygous mutation in the LMNA gene. The proband presented with progressive aggravation of weakness in walking. There was no atrophy of the scapular muscles and the lower-extremity proximal muscles, with normal muscle tension of the extremities, grade 4 muscle strength in the upper and lower extremities, and positive Gower sign. The level of creatine kinase was 779 U/L. Muscle hematoxylin-eosin staining showed muscular dystrophy, and there was no significant reduction in the expression of Lamin A protein. Second-generation sequencing revealed a novel splicing heterozygous mutation, c.810+2T > C, in the LMNA gene, while this locus was normal in his parents. GERP++RS software predicted that the mutation site was highly conservative. Human Splice Finder and Spliceman software predicted that the mutation might be a pathogenic mutation. ExPASy software predicted that the new amino acid sequence became shorter. There were two sequences of mRNA in the patient''s muscle:one was the normal sequence, which accounted for 92.2%; the other was partial intron 4 retention, which was the abnormal splice variant accounting for 7.8%. LGMD1B is a type of autosomal dominant inherited myopathy caused by a mutation in the LMNA gene located on the autosomal 1q22. This study extends the mutation spectrum of the LMNA gene and provides help to the diagnosis of LGMD1B.