Molecular studies on genomic imprinting at APRT locus

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Studies on in vivo somatic mutations at the adenine phosphoribosyltransferase (APRT) locus have disclosed that human somatic cells have mutations at surprisingly high frequencies. Most of the mutations are of the loss of heterozygosity (LOH) type. However, in 3 heterozygotes for APRT deficiency, LOH was not observed suggesting the genomic imprinting at this region. Precise analyzes, however, clarified that the genomic imprinting was not observed in this area, but the 3 persons had a unique deletion mutation which suppressed the occurrence of LOH.By the techniques of selective PCR and inverse PCR,the germline mutation suppressing LOH phenomenon was analyzed. This mutation gene (APRT^<**>del) had a deletion from the intron 4 and was ligated to an unknown gene. The determination of the sequence of the recombination site disclosed that the deletion encompassed at least 2,000 bp and an important gene (tentatively named LSG : LOH-supporter gene) was missing. Thus, when a LSG gene is damaged in the germline as a heterozygous state, then the LOH of the homologous area on the other chromosome is suppressed. The discovery of the new phenomenon for the mechanisms of the suppression of LOH is likely to be applied to various areas. Thus, when a tumor suppressing gene is damaged, a gene therapy destroying a nearby LSG on the same chromosome may successfully suppress the LOH of the other intact chromosome. Such a gene therapy may be useful to treat families with high incidence of cancers. Furthermore, the present type of gene changes may explain the mechanisms of low incidence of tumors in some families.