HAPLOTYPE ANALYSIS OF THE PHENYLALANINE HYDROXYLASE AND PRENATAL DIAGNOSIS OF PKU IN GERMANY

Abstract

Using a full-length cDNA clone for the human phenylalanine hydroxylase (PAH), haplotype analysis of the PAH genes was performed in (20) German PKU-families by determination of the restriction fragment length polymorphism (RFLP). As previously described for another population, an association between normal and mutant PAH-genes and certain haplotypes was observed. The analysis of 8 polymorphic sites detected by the restriction endonucleases revealed that 80% of the normal PAH genes were represented by 5 haplotypes among a possible total of 256 haplotypes. Four of these 5 haplotypes also accounted for greater than 90% of the PKU-genes studied. If each RFLP haplotype is associated with a specific mutation in the PAH gene that causes PKU, the data would suggest that PKU is a heterogeneous disease, and that a great majority of the PKU patients contain only a limited number of different mutant PAH genes in the German population. Indeed, specific RFLP haplotypes appear to be associated with particular disease phenotypes in a limited number of patients studied to date, such that it may be possible to predict the prognosis of disease from the haplotype data of the PKU-genes in the patients. Of 40 obligate carriers studied to date, a RFLP heterozygosity of 87.5% was observed. Since the restriction analysis can be readily performed using chromosomal DNA isolated from amniotic cells or chorionic villi, the data suggest that in 87.5% of the cases, prenatal diagnosis and carrier detection of PKU by gene analysis will be possible in Germany.