Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme

Kinji Ohno, Joan Brengman, Akira Tsujino, Andrew G Engel

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211 Citations (Scopus)

Abstract

In skeletal muscle, acetylcholinesterase (ACHE) exists in homomeric globular forms 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. TheACHE(T) 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 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 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 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 κ10.5S species of AChE composed of one ACHE(T) tetramer and a truncated ColQ strand. The ≃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.

Original languageEnglish (US)
Pages (from-to)9654-9659
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number16
DOIs
StatePublished - Aug 4 1998

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Acetylcholinesterase
Tail
Collagen
Mutation
Enzymes
Basement Membrane
Congenital Myasthenic Syndromes
Complementary DNA
Endplate Acetylcholinesterase Deficiency
Torpedo
COS Cells
Genes
Haplorhini
Rodentia
Catalytic Domain
Skeletal Muscle
Fibroblasts
Kidney
Muscles

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme",
abstract = "In skeletal muscle, acetylcholinesterase (ACHE) exists in homomeric globular forms 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. TheACHE(T) 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 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 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 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 κ10.5S species of AChE composed of one ACHE(T) tetramer and a truncated ColQ strand. The ≃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.",
author = "Kinji Ohno and Joan Brengman and Akira Tsujino and Engel, {Andrew G}",
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T1 - Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme

AU - Ohno, Kinji

AU - Brengman, Joan

AU - Tsujino, Akira

AU - Engel, Andrew G

PY - 1998/8/4

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N2 - In skeletal muscle, acetylcholinesterase (ACHE) exists in homomeric globular forms 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. TheACHE(T) 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 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 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 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 κ10.5S species of AChE composed of one ACHE(T) tetramer and a truncated ColQ strand. The ≃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.

AB - In skeletal muscle, acetylcholinesterase (ACHE) exists in homomeric globular forms 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. TheACHE(T) 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 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 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 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 κ10.5S species of AChE composed of one ACHE(T) tetramer and a truncated ColQ strand. The ≃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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