THE STR252-IVS10NT546-VNTR7 PHENYLALANINE-HYDROXYLASE MINIHAPLOTYPE IN 5 MEDITERRANEAN SAMPLES

IVS10nt546 (IVS10nt-11g-->a) is the most common molecular defect of th e phenylalanine hydroxylase gene causing phenylketonuria in Mediterran ean populations. Previous studies have proposed various and alternativ e hypotheses concerning the geographical origin and pattern of diffusi on of this mutation in this area. Tn this study, this issue was re-exa mined on a large sample (149) of ''Mediterranean'' IVS 10nt536 mutant alleles analysed with multiallelic intragenic polymorphisms. The analy sis of intragenic microsatellite (STR) and minisatellite (VNTR) polymo rphisms shows allelic heterogeneity of the IVS 10nt546 mutation. Eight STR and three VNTR alleles were found in association with the splicin g defect. Of the ten detected STR-VNTR combinations (''minihaplotypes' '), we identified a predominant allelic association (VNTR7 - STR252) e mbedded in a RFLP-haplotype 6 background, which seems to correspond to the ancestral gene originating in the Turkey-Israel area. Analysis of both absolute and relative gene frequencies of the STR252-IVS10nt546 - VNTR7 minihaplotypes, shows statistically significant (P < 0.02) var iations and may suggest gene flow from Turkey and/or Israel to Italy a nd Spain. The associated migratory events need not be unique in time ( and people) but seem to suggest they may be traced back to the expansi on of the Neolithic culture and people, thus allowing dating of the or igin of this mutation to at least 5000-10000 years ago. Alternative hy potheses are discussed to explain, in light of the available historica l and pre-historical evidence, the pattern of diffusion of the IVS 10n t546 mutation in the Mediterranean basin.