MOLECULAR ANALYSIS OF A SERIES OF ALLELES IN HUMANS WITH REDUCED ACTIVITY AT THE TRIOSEPHOSPHATE ISOMERASE LOCUS

Individuals with 50% of expected triosephosphate isomerase (TPI) enzym e activity have been previously identified in families during the scre ening of similar to 2,000 newborn children for quantitative variation in activity of 12 erythrocyte enzymes. The frequency of the trait was 9/1,713 individuals in the Caucasian population and 7/168 individuals among the African-American population studied. Genetic transmission of the trait was confirmed in all families. The frequency of the presump tive deficiency allele(s) at the TPI locus was greater than expected, given the reported incidence of clinical TPI deficiency. We report the molecular characterization of the variant alleles from seven African- American and three Caucasian individuals in this group of unrelated in dividuals. Three amino acid substitutions - a Gly-->Ala substitution a t residue 72, a Val-->Met at residue 154, and a previously described G lu-->Asp substitution at residue 104 - were identified in the Caucasia n individuals. The substitutions occur at residues that are not direct ly involved in the active site but are highly conserved through evolut ionary time, suggesting important roles for these residues in maintena nce of subunit structure and conformation. The variant allele in the s even African-American individuals had nucleotide changes at positions -8 and -5 (5' of) from the transcription-initiation site. In three of these individuals, an additional T-->G substitution was detected in a TATA box-like sequence located 24 nucleotides 5' of the transcription- initiation site and on the same chromosome as the -5/-8 substitutions, Thus, molecular alterations at the TPI locus were detected in 10 unre lated individuals in whom segregation of a phenotype of reduced TPI ac tivity previously had been identified.