Ohno_1998_Proc.Natl.Acad.Sci.U.S.A_95_9654

Reference

Title : Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme - Ohno_1998_Proc.Natl.Acad.Sci.U.S.A_95_9654
Author(s) : Ohno K , Brengman J , Tsujino A , Engel AG
Ref : Proceedings of the National Academy of Sciences of the United States of America , 95 :9654 , 1998
Abstract : In skeletal muscle, acetylcholinesterase (AChE) exists in homomeric globular forms of type T catalytic subunits (ACHET) and heteromeric asymmetric forms composed of 1, 2, or 3 tetrameric ACHET 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 ACHET gene has been cloned in humans; COLQ cDNA has been cloned in Torpedo and rodents but 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 ACHET or the insertion of ColQ into the basal lamina. In six EAD patients, we found no mutations in ACHET. We therefore cloned human COLQ cDNA, determined the genomic structure and chromosomal localization of COLQ, and then searched for mutations in this gene. We identified six recessive truncation mutations of COLQ in six patients. Coexpression of each COLQ mutant with wild-type ACHET in SV40-transformed monkey kidney fibroblast (COS) cells reveals that a mutation proximal to the ColQ attachment domain for ACHET prevents association of ColQ with ACHET; mutations distal to the attachment domain generate a mutant approximately 10.5S species of AChE composed of one ACHET tetramer and a truncated ColQ strand. The approximately 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.
ESTHER : Ohno_1998_Proc.Natl.Acad.Sci.U.S.A_95_9654
PubMedSearch : Ohno_1998_Proc.Natl.Acad.Sci.U.S.A_95_9654
PubMedID: 9689136

Citations formats

Ohno K, Brengman J, Tsujino A, Engel AG (1998)
Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme
Proceedings of the National Academy of Sciences of the United States of America 95 :9654

Ohno K, Brengman J, Tsujino A, Engel AG (1998)
Proceedings of the National Academy of Sciences of the United States of America 95 :9654

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    [paper] => Ohno_1998_Proc.Natl.Acad.Sci.U.S.A_95_9654
    [author] => Ohno K || Brengman J || Tsujino A || Engel AG
    [year] => 1998
    [title] => Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme
    [journal] => Proceedings of the National Academy of Sciences of the United States of America
    [volume] => 95
    [page] => 9654
    [medline] => 9689136
    [abstract] => Ohno_1998_Proc.Natl.Acad.Sci.U.S.A_95_9654
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    [disease_by_interaction] => Endplate Acetylcholinesterase deficiency\; EAD
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            [content] => In skeletal muscle, acetylcholinesterase (AChE) exists in homomeric globular forms of type T catalytic subunits (ACHET) and heteromeric asymmetric forms composed of 1, 2, or 3 tetrameric ACHET 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 ACHET gene has been cloned in humans; COLQ cDNA has been cloned in Torpedo and rodents but 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 ACHET or the insertion of ColQ into the basal lamina. In six EAD patients, we found no mutations in ACHET. We therefore cloned human COLQ cDNA, determined the genomic structure and chromosomal localization of COLQ, and then searched for mutations in this gene. We identified six recessive truncation mutations of COLQ in six patients. Coexpression of each COLQ mutant with wild-type ACHET in SV40-transformed monkey kidney fibroblast (COS) cells reveals that a mutation proximal to the ColQ attachment domain for ACHET prevents association of ColQ with ACHET; mutations distal to the attachment domain generate a mutant approximately 10.5S species of AChE composed of one ACHET tetramer and a truncated ColQ strand. The approximately 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.
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