CHARACTERIZATION OF 12 SILENT ALLELES OF THE HUMAN BUTYRYLCHOLINESTERASE (BCHE) GENE

The silent phenotype of human butyrylcholinesterase (BChE), present in most human populations in frequencies of similar to 1/100,000, is cha racterized by the complete absence of BChE activity or by activity <10 % of the average levels of the usual phenotype. Heterogeneity in this phenotype has been well established at the phenotypic level, but only a few silent BCHE alleles have been characterized at the DNA level. Tw elve silent alleles of the human butyrylcholinesterase gene (BCHE) hav e been identified in 17 apparently unrelated patients who were selecte d by their increased sensitivity to the muscle relaxant succinylcholin e. All of these alleles are characterized by single nucleotide substit utions or deletions leading to distinct changes in the structure of th e BChE enzyme molecule. Nine of the nucleotide substitutions result in the replacement of single amino acid residues. Three of these variant s, BCHE33C, BCHE*198G, and BCHE*-201T, produce normal amounts of immu noreactive but enzymatically inactive BChE protein in the plasma. The other six amino acid substitutions, encoded by BCHE37S, BCHE*125F, BC HE170E, BCHE*471R, and BCHE*518L, seem to cause reduced expression of BChE protein, and their role in determining the silent phenotype was confirmed by expression in cell culture. The other four silent alleles , BCHE271STOP, BCHE*500STOP, BCHE*FS6, and BCHE*I2E3-8G, encode BChEs truncated at their C-terminus because of premature stop codons caused by nucleotide substitutions, a frame shift, or altered splicing. The large number of different silent BCHE alleles found within a relativel y small number of patients shows that the heterogeneity of the silent BChE phenotype is high. The characterization of silent BChE variants w ill be useful in the study of the structure/function relationship for this and other closely related enzymes.