Alternative titles; symbols
HGNC Approved Gene Symbol: BCHE
SNOMEDCT: 360619001;
Cytogenetic location: 3q26.1 Genomic coordinates (GRCh38) : 3:165,772,904-165,837,423 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.1 | {Apnea, postanesthetic, susceptibility to, due to BCHE deficiency} | 617936 | Autosomal recessive | 3 |
| Butyrylcholinesterase deficiency | 617936 | Autosomal recessive | 3 |
Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of choline esters, including the muscle relaxants succinylcholine and mivacurium (summary by Garcia et al., 2011).
Lockridge et al. (1987) concluded that the 4 subunits of cholinesterase are identical and that each contains 574 amino acids and 9 carbohydrate chains attached to 9 asparagines. Prody et al. (1987) isolated and characterized full-length cDNA clones for pseudocholinesterase (butyrylcholinesterase) from human fetal tissues.
McTiernan et al. (1987) screened a cDNA library from human basal ganglia with oligonucleotide probes corresponding to the amino acid sequence of human serum cholinesterase (EC 3.1.1.8), which is also known as acylcholine acylhydrolase. There were 1,722 basepairs of the coding sequence corresponding to the protein found circulating in human serum. The amino acid sequence deduced from the cDNA exactly matched the 574-amino acid sequence of human serum cholinesterase; therefore, the clones represented cholinesterase rather than acetylcholinesterase (ACHE; 100740). Hybridization of genomic DNA blots suggested that a single gene, or very few genes, code for cholinesterase. The amino acid sequences of cholinesterase in brain and serum are apparently identical. Cholinesterase is present in particularly high levels in embryonic and fetal human brain as well as in nervous system tumors such as glioblastomas, neuroblastomas, and meningiomas. The widespread expression in early differentiation suggests development-related functions for this protein.
The BCHE gene contains 4 exons, 3 of which are coding, and spans approximately 64 kb (Arpagaus et al., 1990; Delacour et al., 2014).
On the basis of dosage effects, Arias et al. (1985) suggested that CHE1 is located at chromosome 3q25.2 and that ceruloplasmin (CP; 117700) and TF are nearer the centromere. Using a cDNA clone as a probe for in situ hybridization, Soreq et al. (1987) mapped the CHE1 gene to 3q21-q26.
Gnatt et al. (1990) found that cDNAs made from BCHE mRNA in glioblastoma and nerve blastoma cells map to the same site on 3q where the serum protein polymorphism maps. Furthermore, the asp70-to-gly mutation (177400.0001), which is responsible for the 'atypical' butyrylcholinesterase that is deficient in its capacity to hydrolyze succinylcholine, was identified in an mRNA isolated from glioblastoma tissue.
Both Allderdice et al. (1991) and Gaughan et al. (1991) confirmed localization of the BCHE gene on 3q26. For the study of localization by in situ hybridization in a chromosomal rearrangement, Allderdice et al. (1991) used a different cDNA probe from that used by Soreq et al. (1987). Gaughan et al. (1991) used a PCR-derived probe that included the active site region to give a single hybridization signal by in situ hybridization and refined the localization to 3q26.1-q26.2.
Individuals with the 'silent' cholinesterase phenotype produce a defective enzyme (Liddell et al., 1962) with a different amino acid sequence (Lockridge and La Du, 1986), rendering them particularly sensitive to parathion (p-nitrophenyl diethyl thionophosphate), the agricultural insecticide. Prody et al. (1989) found a 100-fold DNA amplification in the CHE1 gene in a farmer expressing the 'silent' CHE phenotype. DNA blot hybridization with regional cDNA probes suggested that the amplification was most intense in regions encoding central sequences within the gene, whereas distal sequences were amplified to a much lower extent. This is in agreement with the 'onion skin' model, derived from observations on gene amplification in cultured cells and primary tumors. The amplification was absent in the grandparents but present to the same extent in one of their sons and in a grandson, with similar DNA blot hybridization patterns. In situ hybridization experiments localized the amplified sequences to 3q, close to the site of the CHE1 locus. Prody et al. (1989) interpreted these observations as indicating that the initial amplification event occurred early in embryogenesis, spermatogenesis, or oogenesis, where the CHE gene is intensely active and where cholinergic functioning is physiologically necessary. The findings imply that the frequent use of organophosphorous poisons may have long-term inheritable consequences on humans. In spite of the apparent gene amplification, gel electrophoresis and immunoblot analysis of serum proteins with anticholinesterase antibodies failed to reveal overexpression of the protein.
Butyrylcholinesterase deficiency (BCHED; 617936) is most often caused by specific homozygous or compound heterozygous mutation in the BCHE gene. McGuire et al. (1989) found that the 'atypical' dibucaine-resistant BCHE phenotype described by Kalow and Staron (1957) was caused by an asp70-to-gly (D70G; 177400.0001) mutation in the BCHE gene. Homozygosity for D70G or compound heterozygosity for D70G and a silent mutation result in postanesthetic apnea. D70G, which reduces the binding affinity for succinylcholine 100-fold, is the variant most frequently found in cases of prolonged apnea (Lockridge, 2015).
In 7 persons with the 'silent' BCHE phenotype from 2 unrelated families, Nogueira et al. (1989, 1990) identified a homozygous frameshift mutation mutation (177400.0002) in the BCHE gene as the cause of an exaggerated response to succinylcholine.
Bartels et al. (1992) found that the basis of the K-variant phenotype described by Rubinstein et al. (1978) was an ala539-to-thr (A539T; 177400.0005) substitution in the BCHE gene. The allele produced a 30% reduction of serum butyrylcholinesterase activity.
Primo-Parmo et al. (1996) identified 12 silent alleles of the BCHE gene in 17 apparently unrelated patients who were selected by their increased sensitivity to succinylcholine. All of these alleles were characterized by single-nucleotide substitutions or deletions leading to distinct changes in the structure of the enzyme molecule. Replacement of single amino acid residues resulted from 9 of the nucleotide substitutions.
Yen et al. (2003) genotyped 65 Australian patients referred after prolonged post-succinylcholine apnea and identified 52 patients with primary hypocholinesterasemia attributable to BCHE mutations. The most common genotype abnormality was compound homozygous dibucaine (177400.0001)/homozygous K-variant (177400.0005), accounting for 44% of inherited BCHE deficiency. Compound heterozygosity for dibucaine and K-variant was the second most frequent genotype identified; there were no cases of simple homozygosity.
Gatke et al. (2007) identified mutations in the BCHE gene (see, e.g., 177400.0015 and 177400.0016) in patients with BChE deficiency and prolonged apnea after succinylcholine administration.
Feng et al. (1999) generated ColQ (603033) -/- mice to study the roles played by ColQ and AChE in synapses and elsewhere. Such mice failed to thrive and most died before reaching maturity. They completely lacked asymmetric AChE in skeletal and cardiac muscles, specifically at the neuromuscular junction and in the brain. Nonetheless, neuromuscular function was present. A compensatory mechanism appeared to be a partial ensheathment of nerve terminals by Schwann cells. Such mice also lacked the asymmetric forms of Bche. Surprisingly, globular AChE tetramers were absent as well, suggesting a role for the ColQ gene in assembly or stabilization of AChE forms that do not contain a collagenous subunit.
Provisional evidence that the TF-E1 linkage is on chromosome 1 was obtained by Chautard-Freire-Maia (1976). For males the 'Z' value was 1.849 at theta of 0.20 for E1:Rh and 0.595 at theta 0.35 for TF:Rh. The order TF:E1:PGD:Rh:PGM1 was tentatively advanced because close linkage of TF and PGM1 was excluded by the data. Study of a family with both distichiasis and atypical serum cholinesterase indicated that the 2 traits are not closely linked. Assignment of the transferrin (TF; 190000) locus to chromosome 3 by somatic cell hybridization and by comparative mapping indicated that the CHE1 locus is in fact on chromosome 3, not chromosome 1. Primo-Parmo and Chautard-Freire-Maia (1982) excluded linkage of CHE1 and Rh at a theta of less than 0.28.
Some early studies indicated that there were 2 genes for serum cholinesterase, termed E1 (CHE1) and E2 (CHE2), with the E2 gene determining production of an extra enzyme component (the C5 band on starch gel electrophoresis) (Harris et al., 1963). Muensch et al. (1978) observed no difference at the esteratic site of plasma cholinesterase with the C5 component. Several papers mapped the CHE2 locus to chromosome 1 (Merritt et al., 1973), chromosome 13 (Eiberg et al., 1984), chromosome 16 (Lovrien et al., 1978; Soreq et al., 1987; Marazita et al., 1989), and chromosome 2 (Eiberg et al., 1989). A second gene for the C5 phenotype was ruled out by Masson et al. (1990).
Lapidot-Lifson et al. (1989) studied the coamplification of butyrylcholinesterase and acetylcholinesterase (100740) in disorders of platelet production and in leukemia patients. This was thought to indicate that the 2 genes are linked.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). La Du et al. (1991) tabulated the variants, discussed their nomenclature, and gave information on the nature of the molecular defects.
In a review of inheritance and drug response, Weinshilboum (2003) noted that the finding in the late 1950s that impairment in a phase I reaction, namely hydrolysis of the muscle relaxant succinylcholine by butyrylcholinesterase, was inherited served as an early stimulus for the development of pharmacogenetics (Kalow, 1962). At almost the same time, it was observed that a common genetic variation in a phase II pathway of drug metabolism, N-acetylation, could result in striking differences in the half-life and plasma concentrations of drugs metabolized by N-acetyltransferase. The antituberculosis agent isoniazid was the first for which genetic control of metabolism was demonstrated by Evans et al. (1960) (see 243400). Weinshilboum (2003) tabulated 5 phase I and 4 phase II (conjugating) genetically polymorphic enzymes that catalyze drug metabolism and gave selected examples of drugs that have clinically relevant variations in their effects.
McGuire et al. (1989) found that a mutation at nucleotide 209, which changes codon 70 from GAT to GGT, was the abnormality in all 5 atypical cholinesterase families examined. The mutation caused the loss of a Sau3A1 restriction site. The gene change results in a substitution of glycine for aspartic acid as amino acid 70. This is an acidic to neutral amino acid change which accounts for the reduced affinity of atypical cholinesterase for choline esters. Aspartic acid must be an important component of the anionic site.
Atypical BCHE, the classic deficiency variant described by Kalow (1962), Kalow and Gunn (1959), Kalow and Staron (1957), has a homozygote frequency of about 1:3,000 in white North Americans. In the nomenclature system of La Du et al. (1991), this allelic variant is referred to as CHE*70G. The variant has also been described as BCHE*70G and BCHE, dibucaine-resistant I.
Individuals homozygous for the K variant have a normal response to succinylcholine and mivacurium. The K variant is carried by 1 in 4 Caucasians (Lockridge, 2015).
This variant was first described by Liddell et al. (1962). It may have a homozygote frequency of 1:100,000. In 7 persons with the 'silent phenotype' from 2 unrelated families, Nogueira et al. (1989, 1990) identified the mutation responsible for exaggerated response to succinylcholine as a change in the codon for glycine-117: GGT-to-GGAG. This mutation caused a change in the reading frame of +1 and also a stop codon, TGA, 12 amino acids further along, at position 129. These changes are all upstream from the active center serine-198 and would permit production of only 22% of the length of the mature protein. Nogueira et al. (1990) could not demonstrate cross-reactive material. That there are other causes of the silent phenotype was indicated by failure to show the same frameshift mutation in another individual.
This variant has also been designated BCHE ANN ARBOR, CHE*FS117, and BCHE*FS117.
Harris and Whittaker (1961) described this variant which has a homozygote frequency of about 1:150,000. See La Du et al. (1990, 1991) for information on the amino acid substitution. 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. Nogueira et al. (1992) identified 2 different point mutations associated with the fluoride-resistant phenotype. Fluoride-1 has a nucleotide substitution that changes thr243 to met (ACG to ATG).
This variant has also been designated BCHE FLUORIDE-RESISTANT I, CHE*243M, and BCHE*243M.
See La Du et al. (1990, 1991) for information on the amino acid substitution. Nogueira et al. (1992) used DNA sequence analysis of the BCHE gene after amplification by polymerase chain reaction (PCR) to demonstrate a GGT-to-GTT transversion resulting in a gly390-to-val substitution in the fluoride-2 variant.
This variant has also been designated BCHE FLUORIDE-RESISTANT II, CHE*390V, and BCHE*390V.
The K variant of butyrylcholinesterase, named in honor of Werner Kalow, was first recognized through the use of dibucaine inhibition by Rubinstein et al. (1978). They found that the compound heterozygote for the atypical (A, or dibucaine-resistant) gene and the K gene, the AK individual, exhibited lower dibucaine inhibition that did the UA heterozygote (U = usual), because of a one-third reduction in BCHE activity produced by the K-variant allele. Bartels et al. (1992) found that the basis of the K-variant phenotype was a point mutation at nucleotide 1615 that changed codon 539 from GCA (ala) to ACA (thr). The allele produced a 30% reduction of serum butyrylcholinesterase activity. They estimated the frequency of the K-variant allele to be 0.128. They also found that the K-variant mutation was present in 17 of 19 BCHE genes containing the point mutation that causes the atypical phenotype, asp70-to-gly (177400.0001). Rubinstein et al. (1978) and Whittaker and Britten (1988) had estimated the homozygote frequency at 1:100, whereas Evans and Wardell (1984) had placed it somewhat higher, 1:76.
Lehmann et al. (1997) found that the allelic sequence of the gene for the K variant of butyrylcholinesterase was 0.17 in 74 subjects with late-onset Alzheimer disease (AD; 104300), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07), and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon-4 allele of the apolipoprotein E gene, among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 with a 95% confidence interval of 1.65 to 29 in subjects older than 65 years and of 12.8 (1.9 to 86) in subjects older than 75 years. In APOE epsilon-4 carriers over 75 years, only 1 in 22 controls, compared with 10 of 24 confirmed late-onset AD cases, had BCHE-K. Lehmann et al. (1997) suggested that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon-4 as a susceptibility gene for late-onset AD.
Wiebusch et al. (1999) conducted a case-control study of 135 pathologically confirmed AD cases and 70 non-AD controls (age of death greater than or equal to 60 years) in whom they genotyped for APOE epsilon-4 (see 107741) and BCHE-K. The allelic frequency of BCHE-K was 0.13 in controls and 0.23 in cases, giving a carrier odds ratio of 2.1 (95% confidence interval (CI), 1.1-4.1) for BCHE-K in confirmed AD. In an older subsample of 27 controls and 89 AD cases with ages of death greater than or equal to 75 years, the carrier odds ratio increased to 4.5 (95% CI, 1.4-15) for BCHE-K. The BCHE-K association with AD became even more prominent in carriers of APOE epsilon-4. Only 3 of 19 controls compared with 39 of 81 cases carried both, giving an odds ratio of 5.0 (95% CI, 1.3-19) for BCHE-K carriers within APOE epsilon-4 carriers. The authors concluded that the BCHE-K polymorphism is a susceptibility factor for AD and enhances the AD risk from APOE epsilon-4 in an age-dependent manner.
McIlroy et al. (2000) reported a case-control study of 175 individuals with late-onset AD and 187 age- and sex-matched controls from Northern Ireland. The presence of the BCHE K variant was found to be associated with an increased risk of AD (odds ratio = 3.50, 95% CI, 2.20-6.07); this risk increased in subjects 75 years or older (odds ratio = 5.50, 95% CI, 2.56-11.87). No evidence of synergy was found between BCHE K and APOE epsilon-4 in this population.
This variant has also been designated BCHE QUANTITATIVE K POLYMORPHISM, CHE*539T, and BCHE*539T.
The J variant of human serum butyrylcholinesterase causes both an approximately two-thirds reduction of circulating enzyme molecules and a corresponding decrease in the level of BCHE activity in serum. Individuals with the J variant are susceptible to prolonged apnea after succinylcholine. In the family in which Garry et al. (1976) first described the J variant, Bartels et al. (1992) demonstrated an adenine-to-thymine transversion at nucleotide 1490 which changed amino acid 497 from glutamic acid to valine. The J-variant mutation created an RsaI RFLP. The J variant may have a homozygote frequency of about 1:150,000 (Garry et al., 1976; Evans and Wardell, 1984).
This variant has also been designated BCHE QUANTITATIVE J VARIANT.
In 2 unrelated patients seen at Hammersmith Hospital, London, who showed unusual sensitivity to succinylcholine, Whittaker and Britten (1987) identified a BCHE variant that lowered BChE activity by about 90%. Both patients appeared to be heterozygous for the atypical (A) BChE allele (N70G; 177400.0001) coupled with an H variant that conferred very low activity. In 4 individuals from 2 unrelated Danish families with very low levels of BChE, Jensen et al. (1992) found compound heterozygosity for the A variant and the H variant. The H variant was identified as a 424G-A transition resulting in a val142-to-met (V142M) substitution.
This variant has also been designated BCHE QUANTITATIVE H VARIANT.
Simpson and Elliott (1981) described this variant in a single Newfoundland family. The enzyme showed reduced activity. The molecular defect was not identified.
The Cynthiana variant is associated with increased enzyme activity (Yoshida and Motulsky, 1969). Whether it is determined by the E(1) or E(2) locus is not known (Motulsky, 1978). A second example of high activity cholinesterase, apparently identical to BCHE Cynthiana, was reported by Delbruck and Henkel (1979).
Alberti et al. (2010) stated that the mutation responsible for BCHE Cynthiana had not yet been identified.
In a South African Afrikaans-speaking family, Krause et al. (1988) reported a 'new' high activity plasma cholinesterase variant in a mother and son. The variant, which they called E Johannesburg, had the same electrophoretic mobility as the 'usual' enzyme, but greater heat stability. Its higher specific activity was associated with a normal number of enzyme molecules. They could not establish whether the locus involved is E(1) or E(2) or some other locus altogether. BCHE Johannesburg is different from BCHE Cynthiana since increased activities of the latter variant appeared to result from the presence of increased amounts of enzyme protein.
Alberti et al. (2010) stated that the mutation responsible for BCHE Johannesburg had not yet been identified.
Muratani et al. (1991) described inactivation of the cholinesterase gene by an Alu insertion. The patient was a 60-year-old Japanese man who was by chance found to have no cholinesterase activity in his serum when he was hospitalized for diabetes mellitus. By using BCHE cDNA as a probe, Muratani et al. (1991) isolated clones from a genomic library constructed from the patient's DNA. Sequencing showed that exon 2 of the BCHE gene was disrupted by a 342-bp Alu insertion. The Alu element included a poly(A) tract of 38 bp and showed 93% sequence homology with a current type of human Alu consensus sequence. The subject was homozygous and the Alu insertion was inherited in his family. It was flanked by 15 bp of target site duplication in exon 2 corresponding to positions 1062-1076 of the cDNA, indicating that the Alu element could have been integrated by retrotransposition.
Sudo et al. (1997) found low serum BCHE activity on examination of a 63-year-old Japanese man. Secondary hypocholinesterasemia due to agricultural chemical poisoning and severe hepatic dysfunction were excluded. The phenotyping analysis revealed a reduced dibucaine number (DN) and an especially low fluoride number (FN). The investigators identified a homozygous leu330ile (L330I) missense mutation in the BCHE gene of the patient. The DN and FN of recombinant BCHE(L330I) secreted by human fetal kidney cells were compared to recombinant wildtype BCHE and normal serum BCHE. The results established that the L330I amino acid substitution indeed caused the abnormal DN and FN. Sudo et al. (1997) concluded that L330I is a Japanese type fluoride-resistant allele. Individuals heterozygous for the L330I mutation were identified.
Hidaka et al. (1997) demonstrated homozygosity for a tyr128-to-cys (Y128C) amino acid substitution resulting from an A-to-G transition in the BCHE gene. The propositus had extremely low BChE activity, whereas 3 other individuals thought to represent heterozygotes had intermediate or low to normal levels.
Manoharan et al. (2006) tested 226 plasma samples from a Vysya community in India and found that 9 unrelated individuals had no detectable BCHE activity. DNA sequencing revealed that all silent BCHE samples were homozygous for a T-C transition at codon 335 in the BCHE gene, resulting in a leu335-to-pro (L335P) substitution. Expression studies in cell culture confirmed that the mutant was expressed at very low levels. The authors noted that 2 of the silent BCHE individuals were 73 and 80 years old, respectively, demonstrating that absence of BCHE is compatible with long life.
In a patient with butyrylcholinesterase deficiency and prolonged apnea after succinylcholine administration, Gatke et al. (2007) identified a 2-bp deletion (376delCA) in the BCHE gene, resulting in a frameshift and premature termination. The patient's second allele contained a known silent BCHE variant (gly115-to-asp; G115D) (Primo-Parmo et al., 1997) in cis with a novel splice site mutation (177400.0016). BChE activity in the patient was undetectable. This variant has been designated BCHE*FS126.
In a patient with butyrylcholinesterase deficiency and prolonged apnea after succinylcholine administration, Gatke et al. (2007) identified a 2-bp deletion (376delCA; 177400.0015) in the BCHE gene, resulting in a frameshift and premature termination. The patient's second allele contained a known silent BCHE variant (gly115-to-asp; G115D) (Primo-Parmo et al., 1997) in cis with a novel splice site mutation. BChE activity in the patient was undetectable.
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