ADENOSINE-DEAMINASE DEFICIENCY - GENOTYPE-PHENOTYPE CORRELATIONS BASED ON EXPRESSED ACTIVITY OF 29 MUTANT ALLELES

Adenosine deaminase (ADA) deficiency causes lymphopenia and immunodefi ciency due to toxic effects of its substrates. Most patients are infan ts with severe combined immunodeficiency disease (SCID), but others ar e diagnosed later in childhood (delayed onset) or as adults (late onse t); healthy individuals with ''partial'' ADA deficiency have been iden tified. More than 50 ADA mutations are known; most patients are hetero allelic, and most alleles are rare. To analyze the relationship of gen otype to phenotype, we quantitated the expression of 29 amino acid seq uence-altering alleles in the ADA-deleted Escherichia coli strain SO38 34. Expressed ADA activity of wild-type and mutant alleles ranged over five orders of magnitude. The 26 disease-associated alleles expressed 0.001%-0.6% of wild-type activity, versus 5%-28% for 3 alleles from ' 'partials.'' We related these data to the clinical phenotypes and eryt hrocyte deoxyadenosine nucleotide (dAXP) levels of 52 patients (49 imm unodeficient and 3 with partial deficiency) who had 43 genotypes deriv ed from 42 different mutations, including 28 of the expressed alleles. We reduced this complexity to 13 ''genotype categories,'' ranked acco rding to the potential of their constituent alleles to provide ADA act ivity. Of 31 SCID patients, 28 fell into 3 genotype categories that co uld express less than or equal to 0.05% of wildtype ADA activity. Only 2 of 21 patients with delayed, late-onset, or partial phenotypes had one of these ''severe'' genotypes. Among 37 patients for whom pretreat ment metabolic data were available, we found a strong inverse correlat ion between red-cell dAXP level and total ADA activity expressed by ea ch patient's alleles in S circle divide 3834. Our system provides a qu antitative framework and ranking system for relating genotype to pheno type.