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1.
Pharmacogenomics J ; 21(2): 165-173, 2021 04.
Article in English | MEDLINE | ID: mdl-33024248

ABSTRACT

Butyrylcholinesterase (BChE) deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report the characterization of four BCHE mutations associated with prolonged effect of suxamethonium (amino acid numbering based on the matured enzyme): p.20delValPheGlyGlyThrValThr, p.Leu88His, p.Ile140del and p.Arg386Cys. Expression of recombinant BCHE mutants, kinetic analysis and molecular dynamics were undertaken to understand how these mutations induce BChE deficiency. Three of the mutations studied (p.20delValPheGlyGlyThrValThr, p.Ile140del and p.Arg386Cys) lead to a "silent" BChE phenotype. Recombinant BCHE expression studies for these mutants revealed BChE activity levels comparable to untransfected cells. Only the last one (hBChE-L88H) presented BChE activity in the transfected cell culture medium. This BChE mutant (p.Leu88His) is associated with a lower kcat value compare to the wild-type enzyme. Molecular dynamics simulations analyses suggest that a destabilization of a structure implicated in enzyme activity (Ω-loop) can explain the modification of the kinetic parameter of the mutated protein.


Subject(s)
Butyrylcholinesterase/genetics , Mutation/genetics , Succinylcholine/adverse effects , Adult , Aged, 80 and over , Female , Humans , Kinetics , Middle Aged , Mivacurium/adverse effects , Phenotype
2.
Ann Biol Clin (Paris) ; 74(3): 279-85, 2016 Jun 01.
Article in English | MEDLINE | ID: mdl-27237801

ABSTRACT

Butyrylcholinesterase (EC 3.1.1.8; BChE) is a sister enzyme of acetylcholinesterase. Though BChE lacks obvious physiological functions, it is of toxicological and pharmacological importance in detoxifying or catabolising ester-containing drugs. Furthermore, individuals deficient in BChE appear asymptomatic, apart from a heightened sensitivity to the muscle relaxants suxamethonium and mivacurium, two BChE substrates used as myorelaxant. Although many acquired conditions may affect BChE activity, BChE deficiency is mainly due to mutations in the BCHE gene (OMIM 177400). Currently, more than 70 natural mutations have been documented in human BCHE. They have an adverse effect on BChE activity by affecting the catalytic functioning or the protein expression. However, the atypical variant (rs1799807) is the most frequently involved in prolonged apnea.


Subject(s)
Apnea , Butyrylcholinesterase/deficiency , Metabolism, Inborn Errors , Apnea/diagnosis , Apnea/genetics , Apnea/therapy , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/genetics , Butyrylcholinesterase/metabolism , Diagnosis, Differential , Humans , Isoenzymes/chemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/therapy
3.
Ann Biol Clin (Paris) ; 72(5): 543-8, 2014.
Article in French | MEDLINE | ID: mdl-25336127

ABSTRACT

Butyrylcholinesterase (BChE) deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium). Although many acquired conditions may affect BChE activity, BChE deficiency is mainly due to mutations in the BCHE gene (MIM 177400). Though close to 70 natural mutations have been documented in human BCHE, the atypical variant (rs1799807) is the most frequently involved in prolonged apnea. We describe an HRM method for the detection of this variant. Thirty-four patients with known genotype [5 wild-type (U/U), 12 heterozygous (U/A), 17 homozygous (A/A) - A: atypical allele of BCHE, U: usual allele of BCHE -] were screened with the HRM analysis. Within and between-run precision were also evaluated. In silico prediction of HRM curves was performed in order to evaluate the potential impact of the other SNPs described within the PCR product on the HRM diagnostic accuracy. HRM analysis for the BCHE atypical variant genotyping is a simple, rapid, sensitive and low cost method.


Subject(s)
Butyrylcholinesterase/deficiency , Butyrylcholinesterase/genetics , Metabolism, Inborn Errors/genetics , Apnea , Genetic Variation , Genotyping Techniques/methods , Humans , Mutation , Nucleic Acid Denaturation , Time Factors
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