当前位置: X-MOL 学术Eur. J. Hum. Genet. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2020-08-29 , DOI: 10.1038/s41431-020-00715-7
Samantha J Bryen 1, 2 , Emily C Oates 1, 2 , Frances J Evesson 1, 2, 3 , Jessica K Lu 1, 2 , Leigh B Waddell 1, 2 , Himanshu Joshi 1 , Monique M Ryan 4, 5, 6 , Beryl B Cummings 7, 8, 9 , Catriona A McLean 10 , Daniel G MacArthur 7, 8, 9, 11 , Andrew J Kornberg 4, 5 , Sandra T Cooper 1, 2, 3
Affiliation  

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5′ splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.



中文翻译:

致病性深层内含子 MTM1 变异激活编码无义密码子的假外显子,导致严重的 X 连锁肌管肌病。

X 连锁肌管肌病 (XLMTM) 是一种严重的先天性肌病,其特征是全身无力和呼吸功能不全。XLMTM 与MTM1 的致病变异有关;编码脂质磷酸酶肌管蛋白的基因。外显子阴性男性先证者的全基因组测序 (WGS) 具有严重的肌张力减退、呼吸功能不全和肌肉活检集中的细胞核,鉴定出一个深内含子MTM1变体 NG_008199.1(NM_000252.2):c.1468-577A>G,它加强了一个神秘的 5' 剪接位点(+5 位置的 A>G 取代)。由于读取深度低,肌肉 RNA 测序无法诊断。肌肉 RNA 的逆转录 PCR (RT-PCR) 证实 c.1468-577A>G 变体激活了将编码过早终止密码子的伪外显子包含到所有检测到的MTM1转录物中。蛋白质印迹分析确定肌管蛋白缺乏,与严重的 XLMTM 表型一致。我们扩展了 XLMTM 的基因型谱,并强调了在表型一致的 XLMTM 男性先证者中筛选 MTM1 非编码区的好处,这些男性先证者在外显子组测序后仍未确诊。

更新日期:2020-08-29
down
wechat
bug