MUTATION SPECTRUM AND PHENYLALANINE-HYDROXYLASE RFLP VNTR BACKGROUND IN 44 ROMANIAN PHENYLKETONURIC ALLELES/

The mutation spectrum and polymorphic haplotype background in 22 Roman ian families have been analysed in this study using the restriction di gestion of phenylalanine hydroxylase (PAH) regions specifically amplif ied or the DGGE/direct sequencing methods. Eleven PAH mutations specif ically associated with six mutant haplotypes were detected. In spite o f the relative heterogeneity of the molecular defects in the PAH gene, three mutations covered almost 70% of all alleles: R408W, 47.72%, 21/ 44; K363fsdelG 13.63%, 6/44; and P225T 6.81%, 3/44.;. Among these, R40 8W, the most frequent mutation in our population, represented 50% of a ll the phenylketonuric (PKU) chromosomes. Splice mutation IVS12nt1g--> a affected two PAH alleles (4.54%); the remaining seven mutations were rare, each having an effect on just one chromosome (1/44), resulting in a relative frequency of 2.27%, A high frequency was observed in our PKU samples for the relatively uncommon mutations, K363fsdelG and P22 5T mutation, suggesting a possible founder effect at origin. Within th e investigated panel, these mutations, both very rare among other Cauc asians were exclusively linked to haplotype 5.8 and 1.7, respectively. These results provide a basis for the development of a routine molecu lar analysis of Romanian PKU families. (C) 1998 Wiley-Liss, Inc.