ClinVar

DiLella et al. (1987) reported the molecular lesion associated with the RFLP haplotype-2 mutant allele in phenylketonuria (PKU; 261600). This defect is caused by a CGG-to-TGG transition in exon 12, resulting in an amino acid substitution (arg-to-trp) at residue 408 (R408W) of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is in linkage disequilibrium with RFLP haplotype-2 alleles that make up about 20% of mutant PAH genes. This is presumably another example of CpG mutation.

In French Canadians, John et al. (1990) found that the R408W mutation in exon 12 is associated with haplotype 1; in other populations, it occurs on haplotype 2. A CpG dinucleotide is involved in this mutation, compatible with a recurrent mutation, although gene conversion or a single recombination between haplotypes 2 and 1 is possible.

Kalaydjieva et al. (1991) found this mutation in high frequency in Bulgaria, Lithuania, and eastern Germany, where it occurred on haplotype 2. Pooling of data on European populations suggested a Balto-Slavic origin of the R408W defect, with an east-west cline in its frequency.

Tsai et al. (1990) found this mutation in Chinese patients on a different haplotype, namely, no. 44.

Jaruzelska et al. (1991) found that haplotype 2 was most frequently (62%) associated with PKU alleles in Poland where, in the western part of the country, the frequency of PKU is 1 in 5,000 live births. Furthermore, the R408W mutation was in complete linkage disequilibrium with this haplotype. Similar observations have been made in other Eastern European countries such as the former German Democratic Republic, Czechoslovakia, and Hungary. Zygulska et al. (1991) found similar results in southern Poland. Zygulska et al. (1991) found the R408W mutation in 25 of 44 chromosomes from 22 unrelated Polish families with at least 1 PKU child. In 24 of these, mutation was on haplotype 2. A different mutation in the same codon, arg408-to-gln (R408Q; 612349.0038), has been described. Recurrent mutations in the 408 codon appear to occur; at least 2 different mutations (at least mutations on different RFLP haplotype background) have been identified in Chinese patients (Lin et al., 1992). Codon 408 (CGG) contains a CpG hotspot (Ramus et al., 1992). The R408W mutation is a CGG-to-TGG change in the coding strand; the R408Q mutation (612349.0038) is a GCC-to-GTC change in the noncoding strand. Ivaschenko and Baranov (1993) described a rapid and efficient PCR/StyI test for identification of this mutation. Tighe et al. (2003) stated that the R408W mutation in Europe arose by recurrent mutation and is associated with 2 major PAH haplotypes. R408W associated with the 2.3 haplotype exhibits a west-east cline of relative frequency reaching its maximum in the Balto-Slavic region, whereas R408W associated with the 1.8 haplotype exhibits an east-west cline peaking in Connacht, the most westerly province of Ireland. Spatial autocorrelation analysis demonstrated that the 2 clines are consistent with a pattern likely to have been established by human dispersal. Stojiljkovic et al. (2006) identified the R408W mutation in 18% of mutant alleles among 34 unrelated patients with PKU from Serbia and Montenegro. Gersting et al. (2008) stated that the R408W mutation occurs within the catalytic domain of PAH. Unlike wildtype recombinant PAH, which formed tetramers when expressed in E. coli, PAH with the R408W mutation formed high-molecular-mass aggregates, indicative of severe distortion of the protein's oligomeric state.