Wang T, Okano Y, Eisensmith R C, Harvey M L, Lo W H, Huang S Z, Zeng Y T, Yuan L F, Furuyama J I, Oura T
Howard Hughes Medical Institute, Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2146-50. doi: 10.1073/pnas.88.6.2146.
A missense mutation has been identified in the human phenylalanine hydroxylase [PAH; phenylalanine 4-monooxygenase; L-phenylalanine, tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1] gene in a Chinese patient with classic phenylketonuria (PKU). A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro413 for Arg413 in the mutant protein. This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient. Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population. It accounts for 13.8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2.2%) and is absent in the Caucasian population. The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect. Previous protein polymorphism studies in eastern Asia have led to the hypothesis that "northern Mongoloids" represented a founding population in Asia. Our results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations.
在中国一名典型苯丙酮尿症（PKU）患者的人类苯丙氨酸羟化酶[PAH；苯丙氨酸4-单加氧酶；L-苯丙氨酸、四氢生物蝶呤：氧氧化还原酶（4-羟化），EC 1.14.16.1]基因中鉴定出一个错义突变。该基因第12外显子密码子413的第二个碱基处发生G到C的转换，导致突变蛋白中Pro413替代了Arg413。这种突变（R413P）在异源哺乳动物细胞中表达时酶活性可忽略不计，并且与该患者的典型PKU表型相符。群体遗传学研究表明，此突变与限制性片段长度多态性单倍型4紧密连锁，单倍型4是东方人群中PAH基因座的主要单倍型。它占中国北方PKU等位基因的13.8%，日本PKU等位基因的27%，但在中国南方很少见（2.2%），在白种人群体中不存在。这些数据明确表明该突变发生在东方人和白种人种族分化之后，并表明该等位基因通过奠基者效应在整个东方传播。此前在东亚进行的蛋白质多态性研究提出了“北方蒙古人种”是亚洲奠基人群体的假说。我们的结果与这一假说相符，即PKU突变可能发生在北方蒙古人种中，随后传播到中国和日本人群。
