Mutation in the Human Acetylcholinesterase-Associated Collagen Gene, COLQ, Is Responsible for Congenital Myasthenic Syndrome with End-Plate Acetylcholinesterase Deficiency (Type Ic)

• Published in: American journal of human genetics Vol. 63; no. 4; pp. 967 - 975
• Main Authors: Donger, Claire, Krejci, Eric, Pou Serradell, Adolf, Eymard, Bruno, Bon, Suzanne, Nicole, Sophie, Chateau, Danielle, Gary, Françoise, Fardeau, Michel, Massoulié, Jean, Guicheney, Pascale
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-1998
• Subjects: Acetylcholinesterase - deficiency; Acetylcholinesterase - genetics; Adult; Amino Acid Sequence; Chromosome 3p; Chromosome Mapping; Chromosomes, Human, Pair 3; Collagen; COLQ gene; Congenital myasthenic syndrome; Female; Humans; Lod Score; Male; Middle Aged; Molecular Sequence Data; Muscle Proteins; Mutation; Neuromuscular Diseases - genetics; Neuromuscular junction; Neuromuscular Junction - ultrastructure; Pedigree; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Syndrome; Congenital myasthenic syndrome; Acetylcholinesterase deficiency; Chromosome 3p; Neuromuscular junction; COLQ gene
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302059

Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic). It is characterized by onset in childhood, generalized weakness increased by exertion, refractoriness to anticholinesterase drugs, and morphological abnormalities of the neuromuscular junctions (NMJs). The collagen-tailed form of AChE, which is normally concentrated at NMJs, is composed of catalytic tetramers associated with a specific collagen, COLQ. In CMS-Ic patients, these collagen-tailed forms are often absent. We studied a large family comprising 11 siblings, 6 of whom are affected by a mild form of CMS-Ic. The muscles of the patients contained collagen-tailed AChE. We first excluded the
ACHE gene (7q22) as potential culprit, by linkage analysis; then we mapped
COLQ to chromosome 3p24.2. By analyzing 3p24.2 markers located close to the gene, we found that the six affected patients were homozygous for an interval of 14 cM between D3S1597 and D3S2338. We determined the
COLQ coding sequence and found that the patients present a homozygous missense mutation, Y431S, in the conserved C-terminal domain of COLQ. This mutation is thought to disturb the attachment of collagen-tailed AChE to the NMJ, thus constituting the first genetic defect causing CMS-Ic.