In 9 French Canadian patients with hyperphenylalaninemia (see PKU, 261600), John et al. (1989) demonstrated a novel mutation on 5 of the 18 mutant chromosomes: an A-to-G transition (met to val) in codon 1 (M1V), the translation-initiation codon. In all cases the mutation was associated with haplotype 2. A homozygote for this mutation had the PKU phenotype. In 1 proband it was inherited with the splice junction mutation in exon 12 (612349.0001) (on haplotype 3), conferring PKU. In 2 probands it was inherited with a mutation on haplotype 1, conferring PKU in 1 and non-PKU hyperphenylalaninemia in the other.
In contemporary families in France with classic PKU, Lyonnet et al. (1992) found the M1V mutation on 4 of 152 independent chromosomes. All of the French and Quebec M1V mutations occurred on RFLP haplotype 2. The contemporary mutant French chromosomes clustered in southern Brittany (Finistere Sud). Genealogic reconstruction of the Quebec families identified 53 shared ancestors and a center of diffusion in the Perche region in 17th century France. The 2 clusters in France, one historical and the other contemporary, are not incompatible if one assumes the possibility that settlers returned from Nouvelle France or moved from Perche to southern Brittany.
By expression analysis of the M1V mutation, John et al. (1992) demonstrated nondetectable levels of PAH protein and activity.
