Byck S, Tyfield L, Carter K, Scriver C R
McGill University-Montreal Children's Hospital Research Institute, Quebec, Canada.
Hum Mutat. 1997;9(4):316-21. doi: 10.1002/(SICI)1098-1004(1997)9:4<316::AID-HUMU3>3.0.CO;2-3.
The predicted mutability profile (MUTPRED) of the phenylalanine hydroxylase (PAH) gene shows that the 48 CpG sites (template and atemplate strands) are either empty of known mutations (7 sites), harbour "PKU" alleles involving CpG doublets (16 sites), or contain mutations that do not involve a C-->T or G-->A substitution in the doublet. These hypermutable sites harbour 32 different mutations in association with at least 66 different haplotypes and hyperphenylalaninemia. The E280K mutation in exon 7 of the PAH gene is a cause of phenylketonuria. It occurs on four different haplotypes in Europeans and on haplotypes 1 and 2 in Quebec. Whereas a single recombination event could explain the two haplotype associations in Quebec, the mutation does involve a CpG dinucleotide. By analyzing multiallelic markers 5' (STR) and 3' (VNTR) to the E280K allele on 12 mutant and 30 normal chromosomes, we conclude that recurrent mutation is the likely origin of E280K in Quebec. The PAH mutation database shows that the allele accounts for 1.5% of PKU chromosomes worldwide.
苯丙氨酸羟化酶（PAH）基因的预测突变谱（MUTPRED）显示，48个CpG位点（模板链和非模板链）要么没有已知突变（7个位点），要么含有涉及CpG双峰的“苯丙酮尿症（PKU）”等位基因（16个位点），要么含有不涉及双峰中C→T或G→A替换的突变。这些高变位点含有32种不同突变，与至少66种不同单倍型和高苯丙氨酸血症相关。PAH基因第7外显子中的E280K突变是苯丙酮尿症的一个病因。它在欧洲人中有四种不同单倍型，在魁北克存在于单倍型1和2中。虽然一次重组事件可以解释魁北克的两种单倍型关联，但该突变确实涉及一个CpG二核苷酸。通过分析12条突变染色体和30条正常染色体上E280K等位基因5'端（STR）和3'端（VNTR）的多等位基因标记，我们得出结论，反复突变可能是魁北克E280K的起源。PAH突变数据库显示，该等位基因在全球PKU染色体中占1.5%。
