Characterization of four BCHE mutations associated with prolonged effect of suxamethonium

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 (...

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Bibliographic Details
Published in:The pharmacogenomics journal 2021-04, Vol.21 (2), p.165-173
Main Authors: Brazzolotto, Xavier, Courcelle, Sébastien, Sauvanet, Christophe, Guillon, Virginia, Igert, Alexandre, Kononchik, Joseph, Nachon, Florian, Ceppa, Franck, Delacour, Hervé
Format: Article
Language:English
Subjects:
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Adult
Aged, 80 and over
Amino acids
Apnea
Biomedical and Life Sciences
Biomedicine
Butyrylcholinesterase - genetics
Cell culture
Cholinesterases
Complications and side effects
Development and progression
Enzymatic activity
Enzymes
Female
Gene Expression
Gene mutations
Genetic aspects
Health aspects
Human Genetics
Humans
Kinetics
Middle Aged
Mivacurium - adverse effects
Muscle relaxants
Mutants
Mutation
Mutation - genetics
Oncology
Pharmacology, Experimental
Pharmacotherapy
Phenotype
Phenotypes
Psychopharmacology
Succinylcholine
Succinylcholine - adverse effects
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Summary: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 k cat 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.
ISSN:1470-269X
1473-1150
DOI:10.1038/s41397-020-00192-7