Mutation in the Human Acetylcholinesterase-Associated Collagen Gene, COLQ, Is Responsible for Congenital Myasthenic Syndrome with End-Plate Acetylcholinesterase Deficiency (Type Ic)
| Autor: | Jean Massoulié, Michel Fardeau, Suzanne Bon, Sophie Nicole, Claire Donger, Pascale Guicheney, Françoise Gary, Danielle Chateau, Adolf Pou Serradell, Eric Krejci, Bruno Eymard |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Adult
Male Molecular Sequence Data Muscle Proteins Neuromuscular junction Acetylcholinesterase deficiency medicine.disease_cause Polymerase Chain Reaction Congenital myasthenic syndrome chemistry.chemical_compound Chromosome 3p COLQ Genetics medicine Humans CHRNE Missense mutation Genetics(clinical) Amino Acid Sequence Polymorphism Single-Stranded Conformational Genetics (clinical) health care economics and organizations Mutation Sequence Homology Amino Acid biology COLQ gene Chromosome Mapping Neuromuscular Diseases Sequence Analysis DNA Syndrome Middle Aged medicine.disease Acetylcholinesterase Molecular biology Pedigree RAPSN medicine.anatomical_structure chemistry biology.protein Female Chromosomes Human Pair 3 Collagen Lod Score Research Article |
| Zdroj: | The American Journal of Human Genetics. (4):967-975 |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/302059 |
| Popis: | SummaryCongenital 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. |
| Databáze: | OpenAIRE |
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