EVIDENCE FOR FOUNDER EFFECT OF THE GLU104ASP SUBSTITUTION AND IDENTIFICATION OF NEW MUTATIONS IN TRIOSEPHOSPHATE ISOMERASE DEFICIENCY

Triosephosphate isomerase (TPI) deficiency is an autosomal recessive d isorder of glycolysis characterized by multisystem disease and lethali ty in early childhood. Among seven unrelated Northern European kindred s with clinical TPI deficiency studied, a single missense mutation at codon 104 (GAG;Glu --> GAC;Asp) predominated, accounting for 11/14 (79 %) mutant alleles. In three families molecular analysis revealed compo und heterozygosity for Glu104Asp and novel missense mutations. In two cases the second mutation was a Cys to Tyr substitution at codon 41(TG T --> TAT) and in one an Ile to Val substitution at codon 170(ATT --> GTT). The origin of the Glu104Asp mutation was defined by haplotype an alysis using a novel G/A polymorphism at nucleotide 2898 of the TPI ge ne. Cosegregation of the low frequency 2898A allele with the G --> C b ase change at nucleotide 315 supports a single origin for the Glu104As p mutation in a common ancestor. (C) 1997 Wiley-Liss, Inc.