Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene

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-rec...

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Autores principales:	Xiaona Luo, Chunmei Wang, Longlong Lin, Fang Yuan, Simei Wang, Yilin Wang, Anqi Wang, Chao Wang, Shengnan Wu, Xiaoping Lan, Quanmei Xu, Rongrong Yin, Hongyi Cheng, Yuanfeng Zhang, Jiaming Xi, Jie Zhang, Xiaomin Sun, Jingbin Yan, Fanyi Zeng, Yucai Chen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	COLQ gene CMS splicing mutation missense mutation exon deletion Pediatrics RJ1-570
Acceso en línea:	https://doaj.org/article/6939934fb6e9403f8f54ed0089c01920
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spelling	oai:doaj.org-article:6939934fb6e9403f8f54ed0089c019202021-12-01T14:11:13ZMechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene2296-236010.3389/fped.2021.679342https://doaj.org/article/6939934fb6e9403f8f54ed0089c019202021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fped.2021.679342/fullhttps://doaj.org/toc/2296-2360The 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.Xiaona LuoChunmei WangLonglong LinFang YuanSimei WangYilin WangAnqi WangChao WangShengnan WuXiaoping LanQuanmei XuRongrong YinHongyi ChengYuanfeng ZhangJiaming XiJie ZhangXiaomin SunJingbin YanFanyi ZengYucai ChenYucai ChenFrontiers Media S.A.articleCOLQ geneCMSsplicing mutationmissense mutationexon deletionPediatricsRJ1-570ENFrontiers in Pediatrics, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COLQ gene CMS splicing mutation missense mutation exon deletion Pediatrics RJ1-570
spellingShingle	COLQ gene CMS splicing mutation missense mutation exon deletion Pediatrics RJ1-570 Xiaona Luo Chunmei Wang Longlong Lin Fang Yuan Simei Wang Yilin Wang Anqi Wang Chao Wang Shengnan Wu Xiaoping Lan Quanmei Xu Rongrong Yin Hongyi Cheng Yuanfeng Zhang Jiaming Xi Jie Zhang Xiaomin Sun Jingbin Yan Fanyi Zeng Yucai Chen Yucai Chen Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene
description	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.
format	article
author	Xiaona Luo Chunmei Wang Longlong Lin Fang Yuan Simei Wang Yilin Wang Anqi Wang Chao Wang Shengnan Wu Xiaoping Lan Quanmei Xu Rongrong Yin Hongyi Cheng Yuanfeng Zhang Jiaming Xi Jie Zhang Xiaomin Sun Jingbin Yan Fanyi Zeng Yucai Chen Yucai Chen
author_facet	Xiaona Luo Chunmei Wang Longlong Lin Fang Yuan Simei Wang Yilin Wang Anqi Wang Chao Wang Shengnan Wu Xiaoping Lan Quanmei Xu Rongrong Yin Hongyi Cheng Yuanfeng Zhang Jiaming Xi Jie Zhang Xiaomin Sun Jingbin Yan Fanyi Zeng Yucai Chen Yucai Chen
author_sort	Xiaona Luo
title	Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene
title_short	Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene
title_full	Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene
title_fullStr	Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene
title_full_unstemmed	Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene
title_sort	mechanisms of congenital myasthenia caused by three mutations in the colq gene
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/6939934fb6e9403f8f54ed0089c01920
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Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene

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