Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme
Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme
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DOI：
10.1073/pnas.95.16.9654
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发表时间：
1998-08-04
影响因子：
11.1
通讯作者：
Engel, AG
中科院分区：
文献类型：
--
作者：
Ohno, K;Brengman, J;Engel, AG
在骨骼肌中，乙酰胆碱酯酶（AChE）以T型催化亚基（ACHE（T））的同聚球状体和由1、2或3个ACHE（T）四聚体与胶原尾（ColQ）连接而成的异聚不对称形式存在，不对称AChE集中在终板（EP），其胶原尾将其锚定在基膜上。COLQ cDNA已在鱼雷和啮齿类动物中克隆，但在人类中尚未克隆。在致残性先天性肌无力综合征，EP AChE缺乏症（EAD），正常的不对称种类的AChE是缺乏肌肉。EAD可能是由于乙酰胆碱酯酶（ACHE（T））不能与ColQ结合或ColQ插入基底膜的缺陷所致。在6例EAD患者中，我们未发现ACHE（T）突变。每种COLS突变体与野生型ACHE（T）在SV 40转化的猴肾成纤维细胞（COS）中的共表达揭示了ACHE（T）的ColQ附着结构域附近的突变阻止了ColQ与ACHE（T）的关联;连接结构域远端的突变产生了由一个ACHE（T）四聚体和截短的ColQ链组成的近似10.5S种类的AChE突变体，大约10.5S的种类缺乏部分胶原结构域和ColQ的整个C末端结构域，或者它们仅缺乏形成三重胶原螺旋所需的C末端结构域，这可能阻止它们插入基底层。
In skeletal muscle, acetylcholinesterase (AChE) exists in homomeric globular Terms of type T catalytic subunits (ACHE(T)) and heteromeric asymmetric forms composed of 1, 2, or 3 tetrameric ACHE(T) attached to a collagenic tail (ColQ).Asymmetric AChE is concentrated at the endplate (EP), where its collagenic tail anchors it into the basal lamina, The ACHE(T) gene has been cloned in humans; COLQ cDNA has been cloned in Torpedo and rodents hut not in humans. In a disabling congenital myasthenic syndrome, EP AChE deficiency (EAD), the normal asymmetric species of AChE are absent from muscle. EAD could stem from a defect that prevents binding of ColQ to ACHE(T) or the insertion of ColQ into the basal lamina, In six EAD patients, we found no mutations in ACHE(T), We therefore cloned human COLQ cDNA, determined the genomic structure and chromosomal localization of COLO, and then searched for mutations in this gene, We identified six recessive truncation mutations of COLQ in six patients. Coexpression of each COLS mutant with wild-type ACHE(T) in SV40-transformed monkey kidney fibroblast (COS) cells reveals that a mutation proximal to the ColQ attachment domain for ACHE(T) prevents association of ColQ with ACHE(T); mutations distal to the attachment domain generate a mutant approximate to 10.5S species of AChE composed of one ACHE(T) tetramer and a truncated ColQ strand, The approximate to 10.5S species lack part of the collagen domain and the entire C-terminal domain of ColQ, or they lack only the C-terminal domain, which is required for formation of the triple collagen helix, and this likely prevents their insertion into the basal lamina.