Founder effect of a prevalent phenylketonuria mutation in the Oriental population.
Founder effect of a prevalent phenylketonuria mutation in the Oriental population.
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东方人群中普遍存在的苯丙酮尿症突变的创始人效应。
DOI：
10.1073/pnas.88.6.2146
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发表时间：
1991
影响因子：
11.1
通讯作者：
Oura,T
中科院分区：
文献类型：
--
作者：
Wang,T;Okano,Y;Eisensmith,RC;Harvey,ML;Lo,WH;Huang,SZ;Zeng,YT;Yuan,LF;Furuyama,JI;Oura,T
人类苯丙氨酸羟化酶[PAH；苯丙氨酸4-monooxygenase;l -苯丙氨酸，四氢生物蝶呤：氧氧化还原酶（4-羟基化），EC 1.14.16.1]基因在中国典型苯丙酮尿症（PKU）患者中的表达。该基因第12外显子413密码子第二碱基的G-to-C转换导致突变蛋白中的Pro413取代Arg413。这种突变（R413P）在异源哺乳动物细胞中表达时，酶活性可以忽略不计，并且与患者的典型PKU表型兼容。群体遗传学研究表明，该突变与限制性内切片段长度多态性单倍型4密切相关，该单倍型是东方人群PAH位点的优势单倍型。它占中国北方13.8%和日本27%的PKU等位基因，但在中国南方很少见（2.2%），在高加索人群中不存在。数据明确表明，突变发生在东方人和高加索人的种族分化之后，表明该等位基因通过奠基人效应在整个东方传播。先前对东亚的蛋白质多态性研究提出了“北方蒙古人种”代表亚洲创始人群的假设。我们的结果与这一假设相一致，因为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。
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.