PHENYLKETONURIA MUTATIONS AND THEIR RELATION TO RFLP HAPLOTYPES AT THE PAH LOCUS IN CZECH PKU FAMILIES

A detailed study of the mutant phenylalanine hydroxylase (PAH) gene fr om the eastern part of the Czech Republic (Moravia) is reported. A tot al of 190 mutant alleles from 95 phenylketonuria (PKU) families were a nalyzed for 21 prevalent Caucasian mutations and restriction fragment length polymorphism /variable number of tandem repeats (RFLP/VNTR) hap lotypes. Eighty per cent of all mutant alleles were found to carry 11 mutations. The most common molecular defect was the mutation R408W (55 .3%), with a very high degree of homozygosity (34.6%). Each of four ot her mutations (R158Q, R243X, G272X, IVS12nt1) accounted for more than 3% of PKU alleles. Rarely present were mutations IVS10nt546 (2.6%), R2 52W (2.6%), L48S (2.1%), R261Q (1.6%), Y414C (1.0%) and I65T (0.5%). M utations that have been predominantly described in southern Europe (IV S7nt1, A259V, Y277D, R241H, T278N) were not detected. A total of 14 di fferent mutant haplotypes were observed. Three unusual genotype-haplot ype associations were identified (R158Q on haplotypes 2.3 and 7.8 and R252W on haplotype 69.3). There was a strong association between the m utation R408W and haplotype 2.3 (54.7%). Heterogeneity was found at mu tations R408W (haplotypes 2.3 and 5.9), R158Q (haplotypes 4.3, 2.3 and 7.8) and IVS10nt546 (haplotypes 6.7 and 34.7). The molecular basis of PKU in the Moravian area appears to be relatively homogeneous in comp arison with other southern and western European populations, thus prov iding a good starting point for prenatal diagnosis and early clinical classification.