Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations

Autor: Claudio Mazia, Constance M. Bowe, Maria Magdalena Vaccarezza, Ricardo A. Maselli, Marian Lara, Marcela Garcia-Erro, Juan Arredondo, Sidney M. Gospe, Michelle M. Mezei, Celia H. Chang
Rok vydání: 2015
Předmět:
Male
Models
Molecular
genotype-phenotype correlations
Protein Conformation
DNA Mutational Analysis
Gene Expression
medicine.disease_cause
Substrate Specificity
Congenital
Models
enzyme kinetics
Catalytic Domain
Genotype
Gene expression
2.1 Biological and endogenous factors
Aetiology
Phosphorylation
Child
Genetics (clinical)
Genetics & Heredity
Mutation
Congenital myasthenic syndrome
Phenotype
Choline acetyltransferase
Child
Preschool
Myasthenic Syndromes
Female
Acetylcholine
medicine.drug
medicine.medical_specialty
Adolescent
Clinical Sciences
Biology
Article
Choline O-Acetyltransferase
Rare Diseases
Internal medicine
Myasthenia Gravis
Genetics
medicine
Humans
Allele
Preschool
Alleles
Genetic Association Studies
Myasthenic Syndromes
Congenital
Binding Sites
Neurosciences
Molecular
Hydrogen Bonding
medicine.disease
Enzyme Activation
HEK293 Cells
Endocrinology
ChAT
Amino Acid Substitution
nervous system
Zdroj: Human mutation, vol 36, iss 9
ISSN: 1059-7794
DOI: 10.1002/humu.22823
Popis: Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes.
Databáze: OpenAIRE
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