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1例肢带型肌营养不良1B型的临床和遗传学特点
Clinical and genetic features of limb-girdle muscular dystrophy type 1B: a case report
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。
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.
肢带型肌营养不良1B型 / LMNA基因 / 剪接突变 / 儿童
Limb-girdle muscular dystrophy type 1B / LMNA gene / Splicing mutation / Child
[1] Wicklund MP, Kissel JT. The limb-girdle muscular dystrophies[J]. Neurol Clin, 2014, 32(3):729-749.
[2] 杨钊, 董继宏. 常染色体显性遗传性肢带型肌营养不良症研究进展[J]. 中国临床神经科学, 2016, 24(1):84-88.
[3] Thompson R, Straub V. Limb-girdle muscular dystrophies-international collaborations for translational research[J]. Nat Rev Neurol, 2016, 12(5):294-309.
[4] Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B)[J]. Hum Mol Genet, 2000, 9(9):1453-1459.
[5] Janin A, Bauer D, Ratti F, et al. SMAD6 overexpression leads to accelerated myogenic differentiation of LMNA mutated cells[J]. Sci Rep, 2018, 8(1):5618.
[6] Lim KH, Fairbrother WG. Spliceman--a computational web server that predicts sequence variations in pre-mRNA splicing[J]. Bioinformatics, 2012, 28(7):1031-1032.
[7] Davydov EV, Goode DL, Sirota M, et al. Identifying a high fraction of the human genome to be under selective constraint using GERP++[J]. PLoS Comput Biol, 2010, 6(12):1-13.
[8] Worman HJ. Nuclear lamins and laminopathies[J]. J Pathol, 2011, 226(2):316-325.
[9] Mercuri E, Brown SC, Nihoyannopoulos P, et al. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene[J]. Muscle Nerve, 2005, 31(5):602-609.
[10] Seong MW, Cho A, Park HW, et al. Clinical applications of next-generation sequencing-based gene panel in patients with muscular dystrophy:Korean experience[J]. Clin Genet, 2016, 89(4):484-488.
[11] 何展文, 曾乐翔, 刘木金, 等. 肌肉活检病理检查在小儿神经肌肉疾病中的应用[J]. 实用医学杂志, 2015, 31(23):3918-3920.
[12] Maraldi NM, Capanni C, Cenni V, et al. Laminopathies and lamin-associated signaling pathways[J]. J Cell Biochem, 2011, 112(4):979-992.
[13] van Engelen BG, Muchir A, Hutchison CJ, et al. The lethal phenotype of a homozygous nonsense mutation in the lamin A/C gene[J]. Neurology, 2005, 64(2):374-376.
[14] Geiger SK, Bar H, Ehlermann P, et al. Incomplete nonsense-mediated decay of mutant lamin A/C mRNA provokes dilated cardiomyopathy and ventricular tachycardia[J]. J Mol Med (Berl), 2008, 86(3):281-289.
[15] Rankin J, Ellard S. The laminopathies:a clinical review[J]. Clin Genet, 2006, 70(4):261-274.
[16] Rogozhina Y, Mironovich S, Shestak A, et al. New intronic splicing mutation in the LMNA gene causing progressive cardiac conduction defects and variable myopathy[J]. Gene, 2016, 595(2):202-206.
[17] Todorova A, Halliger-Keller B, Walter MC, et al. A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B[J]. J Med Genet, 2003, 40(10):e115.
