p.T243M Thr243Met (p.T271M Thr271Met in primary sequence with 28 amino-acids signal peptide) (from OMIM) Fluoride-resistant I, F-1 CHE*243M Harris and Whittaker (1961) described this variant which has a homozygote frequency of about 1:150,000. The fluoride variant of human butyrylcholinesterase owes its name to the observation that it is resistant to inhibition by 0.050 mM sodium fluoride in the in vitro assay. Individuals who are compound heterozygotes for the fluoride and atypical alleles experience about 30 min of apnea, rather than the usual 3-5 min, after receiving succinyldicholine.
Kinetic parameters
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References:
Title: Naturally occurring mutation, Asp70his, in human butyrylcholinesterase Boeck AT, Fry DL, Sastre A, Lockridge O Ref: Annals of Clinical Biochemistry, 39:154, 2002 : PubMed
BACKGROUND: People with genetic variants of butyrylcholinesterase can have hours of prolonged apnoea after a normal dose of succinylcholine or mivacurium. METHODS: Serum samples from 308 persons living in mid-USA were phenotyped to identify the atypical and fluoride variants. 308 samples were analysed for the K variant by DNA amplification, digestion with Mae III and gel electrophoresis. Amplified DNA from 16 samples was sequenced to identify the D70G, T243M and D70H mutations. Values for kcat and Km were determined for the D70H mutant BChE expressed in 293T cells. RESULTS: A new mutation, Asp70His, was identified. This mutation is located in the peripheral anionic site of butyrylcholinesterase, where it causes a 10-fold decrease in binding affinity for positively charged substrates. CONCLUSION: People homozygous for the Asp70His mutation are expected to have prolonged apnoea in response to succinylcholine or mivacurium, similar to people with the Asp70Gly mutation.
The fluoride variant of human butyrylcholinesterase owes its name to the observation that it is resistant to inhibition by 0.050 mM sodium fluoride in the in vitro assay. Individuals who are heterozygous for the fluoride and atypical alleles experience about 30 min of apnea, rather than the usual 3-5 min, after receiving succinyldicholine. Earlier we reported that the atypical variant has a nucleotide substitution which changes Asp 70 to Gly. In the present work we have identified two different point mutations associated with the fluoride-resistant phenotype. Fluoride-1 has a nucleotide substitution which changes Thr 243 to Met (ACG to ATG). Fluoride-2 has a substitution which changes Gly 390 to Val (GGT to GTT). These results were obtained by DNA sequence analysis of the butyrylcholinesterase gene after amplification by PCR. The subjects for these analyses were 4 patients and 21 family members.
Title: Differential inhibition of serum cholinesterase with fluoride. Recognition of two new phenotypes Harris H, Whittaker M Ref: Nature, 191:496, 1961 : PubMed
