INTERVENTION OF SOMATIC MUTATIONAL EVENTS IN-VIVO BY A GERMLINE DEFECT AT THE ADENINE PHOSPHORIBOSYLTRANSFERASE LOCUS

Both germline and somatic mutations are known to affect phenotypes of human cells in vivo. In previous studies, we cloned mutant peripheral blood T cells from germline heterozygous humans for adenine phosphorib osyltransferase (APRT) (EC 2.4.2.7) deficiency and found that approxim ately 1.3x10(-4) peripheral T cells had undergone in vivo somatic muta tions. Loss of heterozygosity (LOH) was the major cause of the mutatio ns at the APRT locus since approximately 80% of the mutant T cell clon es exhibited loss of normal alleles. Ln the present study, we identifi ed three heterozygous individuals for APRT deficiency (representing tw o separate families), in whom none of the somatic mutant cells exhibit ed LOH at the APRT locus. The germline mutant APRT alleles of these he terozygotes from two unrelated families had the same gross DNA abnorma lities detectable by Southern blotting. None of the germline mutant AP RT alleles so far reported had such gross DNA abnormalities. The data suggest that the germline mutation unique to these heterozygous indivi duals is associated with the abrogation of LOH in somatic cells. The a bsence of LOH at a different locus has already been reported in vitro in an established cell line but the present study describes the first such event in vivo in human individuals.