p.V142M Val142Met (p.V170M Val170Met in primary sequence with 28 amino-acids signal peptide) The H-variant (H variant) is a quantitative variant that reduces enzymatic activity by approximatively 90% Whittaker and Britten. The mutation was found in a patient compound heterozygote together with 328D_human-BCHE Gatke et al.
Kinetic parameters
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References:
Title: Two novel mutations in the BCHE gene in patients with prolonged duration of action of mivacurium or succinylcholine during anaesthesia Gatke MR, Bundgaard JR, Viby-Mogensen J Ref: Pharmacogenet Genomics, 17:995, 2007 : PubMed
BACKGROUND: Butyrylcholinesterase (BChE) hydrolyses the neuromuscular blocking agents, succinylcholine and mivacurium used during general anaesthesia. Hereditary low BChE activity may result in an extensively prolonged duration of action of these drugs, especially in patients who are homozygous for the atypical or silent variants. We present three novel mutations in the butyrylcholinesterase gene (BCHE) identified in three families in which a member had experienced severely prolonged duration of action of succinylcholine. METHODS: As the phenotypes of the three probands could not be established with certainty using conventional biochemical tests, DNA samples were collected from two of the probands and four relatives. Genotypes were determined using complete nucleotide sequencing. RESULTS: Three novel mutations were identified: BCHE*FS126, BCHE*I3E4-14C and BCHE*328D. The proband in family 1 was genotyped as BCHE*115D*I3E4-14C/BCHE*FS126, whereas the proband in family 3 was compound heterozygous for BCHE*328D and BCHE*142M. In both patients, BChE activity was below detection limit, and they experienced an extensively prolonged duration of action of succinylcholine. The proband in family 2 was not sequenced, but a relative was heterozygous for BCHE*FS126. BCHE*I3E4-14C was in linkage with a known silent variant. CONCLUSIONS: Two novel variants of BCHE are silencing the enzyme function. BCHE*FS126 results in a truncated protein lacking the active site and is therefore inactive. The second variant is BCHE*328D, also resulting in an inactive protein, as this change in amino acid is radical and furthermore situated in the gorge harbouring the active site. These variants result in extensively prolonged duration of action of succinylcholine.
Title: Structural basis of the butyrylcholinesterase H-variant segregating in two Danish families Jensen FS, Bartels CF, La Du BN Ref: Pharmacogenetics, 2:234, 1992 : PubMed
The rare H-variant of human butyrylcholinesterase is a quantitative variant that reduces serum butyrylcholinesterase activity by about 90%. Individuals who are heterozygous for both the H-variant and the atypical variant are abnormally sensitive to the muscle relaxant succinylcholine. By using standard phenotypic serum assays, the Danish Cholinesterase Research Unit identified four individuals from two unrelated pedigrees who were heterozygous for both the H-variant (H) and the atypical (A) variant. DNA of these A/H individuals was extracted from white blood cells. Using the polymerase chain reaction and subsequent DNA sequencing, a point mutation was found at nucleotide 424 which changed amino acid 142 from valine to methionine. The previously identified atypical mutation, Asp 70 to Gly, was also seen, which segregated apart from the H-variant mutation in family studies. These two mutations were found in all four A/H individuals.
Title: E1h, a new allele at cholinesterase locus 1 Whittaker M, Britten JJ Ref: Hum Hered, 37:54, 1987 : PubMed
Unusual inhibition characteristics in two unrelated suxamethonium-sensitive individuals were indicative of a new allele, E1h, segregating with the E1a gene. Family studies substantiate this hypothesis and three new genotypes are recognised.
The H-variant (H variant) is a quantitative variant that reduces enzymatic activity by approximatively 90%