Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene.
Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene.
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DOI：
10.3389/fped.2021.679342
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发表时间：
2021
影响因子：
2.6
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Luo X;Wang C;Lin L;Yuan F;Wang S;Wang Y;Wang A;Wang C;Wu S;Lan X;Xu Q;Yin R;Cheng H;Zhang Y;Xi J;Zhang J;Sun X;Yan J;Zeng F;Chen Y
编码不对称乙酰胆碱酯酶(COLQ)胶原样尾部亚单位的基因负责乙酰胆碱酯酶三条胶原蛋白的转录，这些胶原蛋白连接在神经肌肉接头的终板上。COLQ基因突变以常染色体-隐性遗传方式遗传，可导致V型先天性肌无力综合征(CMS)，表现为出生时或出生后不久肌肉力量下降，呼吸衰竭，眼睛运动受限，眼皮下垂和吞咽困难。在这里，我们报告了两名无血缘关系的CMS儿童的COLQ中的三个变异。在一名13个月大的男婴中，发现一个内含子突变(c.393+1G>；A)和一个新的错义突变(p.Q381P)为复合杂合子，父母均为携带者。在一名12岁男孩中发现了包括外显子14和15在内的基因内缺失，处于纯合子状态。我们研究了COLQ和AChE基因在先证者家庭中的相对表达，进行了三维蛋白质结构分析，并分析了错义突变C.1142A和GT；C(p.Q381P)的保守性。剪接突变c.393+1G>；A影响COLQ外显子5的正常剪接，导致27bp的缺失。错义突变c.1142a>；C(p.Q381P)在不同物种中处于保守位置。我们发现COLQ外显子14-15的纯合子缺失导致了241个碱基的缺失，这减少了氨基酸的数量，并导致了移码翻译。先证者的COLQ表达显著低于先证者的父母和兄弟姐妹，而AChE的表达显著高于先证者的父母和兄弟姐妹。此外，这些突变被发现在预测的蛋白质三维结构上造成显著差异。剪接突变c.393+1G>；A、错义突变c.1a>；C(p.Q381P)、COLQ外显子14-15缺失均可引起CMS。
The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.
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影响因子：
5.1
作者：
Ohno, Kinji;Ito, Mikako;Kawakami, Yu;Krejci, Eric;Engel, Andrew G.
通讯作者：
Engel, Andrew G.
影响因子：
5.3
作者：
Sigoillot, Severine M.;Bourgeois, Francine;Legay, Claire
通讯作者：
Legay, Claire
影响因子：
5.3
作者：
Arredondo, Juan;Lara, Marian;Ng, Fiona;Gochez, Danielle A.;Lee, Diana C.;Logia, Stephanie P.;Joanna Nguyen;Maselli, Ricardo A.
通讯作者：
Maselli, Ricardo A.
影响因子：
3.5
作者：
McMacken, Grace M.;Spendiff, Sally;Lochmuller, Hanns
通讯作者：
Lochmuller, Hanns
DOI：
10.1111/j.1432-1033.2004.04052.x
发表时间：
2004-04-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Belbeoc'h, S;Falasca, C;Bon, S
通讯作者：
Bon, S