Lee Seungbok, Eum Juneyong, Park Soojin, Ki Seoyoung, Hwang Byung Joon, Kee Yun, Chae Jong Hee
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101 Daehakro Jongno-gu, 03080 Seoul, Republic of Korea.
Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
Neuromuscul Disord. 2022 Feb;32(2):176-184. doi: 10.1016/j.nmd.2021.12.003. Epub 2021 Dec 16.
Nemaline myopathies are clinically and genetically heterogeneous disorders caused by several different genes. One of them is TNNT1, which was initially described in Amish families and has not been reported in Asian populations. Although most TNNT1 myopathies are caused by loss-of-function mutations, several recent studies have shown that missense mutations can also be pathogenic. A 16-year-old Korean boy with progressive muscle weakness visited the Seoul National University Hospital. He showed generalized myopathy, which was predominant in the paraspinal and neck muscles. Moreover, nemaline rods were observed in a muscle biopsy. Whole-exome sequencing of DNA samples of the patient and his younger brother, who had a similar phenotype, revealed novel compound heterozygous mutations in TNNT1 (c.724G>C (p.Ala242Pro) and c.611+1G>A). Sanger sequencing of cDNA extracted from muscle samples of the patient confirmed partial or total skipping of exon 11 in the splicing variant. The impact of the missense variant on muscle integrity and locomotor activity was verified using a zebrafish loss-of-function model. Here, we reported novel familial cases of TNNT1 myopathy with intermediate clinical presentations caused by compound heterozygous mutations and demonstrated their functional defects using an animal model.
杆状体肌病是由几种不同基因引起的临床和遗传异质性疾病。其中之一是TNNT1,最初在阿米什家族中被描述,尚未在亚洲人群中报道。尽管大多数TNNT1肌病是由功能丧失突变引起的,但最近的几项研究表明,错义突变也可能具有致病性。一名16岁进行性肌肉无力的韩国男孩前往首尔国立大学医院就诊。他表现出全身性肌病,以椎旁肌和颈部肌肉为主。此外,在肌肉活检中观察到杆状体。对该患者及其具有相似表型的弟弟的DNA样本进行全外显子组测序,发现TNNT1存在新的复合杂合突变(c.724G>C(p.Ala242Pro)和c.611+1G>A)。对从患者肌肉样本中提取的cDNA进行桑格测序,证实剪接变体中外显子11部分或完全跳跃。利用斑马鱼功能丧失模型验证了错义变体对肌肉完整性和运动活性的影响。在此,我们报告了由复合杂合突变引起的具有中间临床表现的TNNT1肌病新的家族病例,并使用动物模型证明了它们的功能缺陷。