POLYMORPHIC DNA HAPLOTYPES AT THE PHENYLALANINE-HYDROXYLASE (PAH) LOCUS IN ASIAN FAMILIES WITH PHENYLKETONURIA (PKU)

  • 1 August 1989
    • journal article
    • research article
    • Vol. 45  (2) , 319-324
Abstract
DNA polymorphisms at the phenylalanine hydroxylase (PAH) locus have proved highly effective in linkage diagnosis of phenylketonuria (PKU) in Caucasian families. More than 10 RFLP sites have been reported within the PAH structural locus in Caucasians. With information from affected and unaffected offspring in PKU families it is often posisble to reconstruct complete RFLP haplotypes in parents and to use these haplotypes to follow the segregation of PKU within families and to determine the distribution of PKU chromosomes within populations. To establish the utility of these RFLPs in characterizing Asian families with PKU, we typed eight DNA sites in 21 Chinese families and 12 Japanese families with classical PKU. The eight RFLPs were chosen for their informativeness in Caucasians. From these families we reconstructed a total of 91 complete PHA haplotypes, 44 from non-PKU chromosomes and 47 from PKU-bearing chromosomes. Although all eight marker sites are polymorphic in both Chinese and Japanese, there is much less haplotypic varitation in Asians than in Caucasians. In particular, one haplotype alone, haplotype 4, accounts for more than 77% of non-PKU chromosomes and for more than 80% of PKU-bearing chromosomes. Haplotype 4 is also relatively common in Caucasians. The next most common Asian haplotype is 10 times less frequent than haplotype 4. By contrast, in many Caucasian populations the sum of the frequencies of the five most common haplotypes is still less than 80%, and several of the most common haplotypes are equally frequent. Even though the extent of haplotypic variation in Asians is severely limited, the few haplotypes that are found often differ at a number of RFLP sites. This acocunts for the observation that haplotypes show little variation in Chinese and Japanese but that the individual RFLP sites are all polymorphic in both populations. It appears that these RFLPs predate the separation of Asian and Caucasians but that the haplotypic variation has either decreased or increased in one or the other racial group since then. Although the PAH RFLPs and haplotypes will not be as useful in Asian familieswith PKU as in Caucasian families with PKU, at least 36% aof Asian carriers of PKU are heterozygous.sbd.and hence informative.sbd.at one or more RFLP sites.