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Genetic diversity from a limited repertoire of mutations on different common allelic backgrounds: α 1 ‐antitrypsin deficiency variant P duarte
Author(s) -
Hildesheim J.,
Kinsley G.,
Bissell M.,
Pierce J.,
Brantly M.
Publication year - 1993
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1380020311
Subject(s) - biology , repertoire , genetics , allele , diversity (politics) , genetic diversity , mutation , evolutionary biology , gene , population , physics , demography , sociology , anthropology , acoustics
α 1 ‐Antitrypsin (α1AT) is one of the most polymorphic gene loci in the human genome. α l AT variants are typically identified by their migration position in an isoelectric focusing gel at pH 4–5. Heterogeneity of the isoelectric point of α1AT variants, hence variant migration, most often results from amino acid substitutions which alter the net charge of the molecule. We identified an individual heterozygous for an α1AT variant migrating in the “P” variant region which differs from other known “P” variants. Using isoelectric focusing on an immobilized pH gradient at pH 4.50–4.85 the novel P allele, P duarte migrates between P st. albans and P lowell . Densitometric analysis of normal “M” type α1AT and the deficiency variant P lowell major bands separated by isoelectric focusing demonstrates that P duarte contributes approximately 41% as much α1AT to the total serum α1AT concentration as the normal “M” α1AT, similar to P lowell . Direct DNA sequencing of the proband's genomic DNA demonstrates that the P duarte allele differs from the normal M1(V213) allele by two amino acid substitutions, R101 (C G T→ H(C A T) and D256 (G A T)→V (G T T). Individually, these amino acid substitutions characterize the normal M4 allele (R101→H) and the deficient P lowell allele (D256→V). Thus the P duarte allele differs from the P lowell allele only by the normal allelic background in which the V256 mutation occurs. Comparison of amino acid sequences among several α1AT variants demonstrates that P duarte is an example of a more general observation regarding diversity within the PI (protease inhibitor) systems. It is apparent that the heterogeneity observed among α1AT variants is due in part to combinations of a limited repertoire of amino acid substitutions. These combinations may be the product of mutational hot spots and/or recombination on normal allelic backgrounds. © 1993 Wiley‐Liss, Inc.