Molecular Analysis of Phenylketonuria in East Asians

苯丙酮尿症(PKU)是一种由肝苯丙氨酸羟化酶(PAH)缺乏引起的常染色体隐性遗传病。全世界已经发现了100多种不同的突变，并发现PKU是一种高度异质性的疾病。我对东亚地区的PKU进行了分子分析。我已经确定了东亚人60%的PKU等位基因有10个PKU突变。两个主要的PKU突变，R413P和IVS4nt-1，可能起源于不同的人群，在史前时代传播到亚洲大陆。我在高加索人和东亚人之间发现了不同的突变，因此在高加索人和东亚人之间的种族分化之后发生了PKU突变。此外，表达分析中的PKU基因型和体外PAH活性与东亚人的临床和生化表型相关。PAH基因上的分子缺陷调节体内PAH的活性和临床表现。由于PAH只在肝脏表达，因此不合法的转录有助于检测几个PKU突变。通过对两个错义突变(R241C、R408Q)的分析，发现了两个错义突变(R241C、R408Q)，并通过分析PAH基因和基因组DNA，发现了一个由无义突变(Y356X)引起的剪接突变和10kb的基因组DNA缺失。短串联重复序列杂合率为70%，可用于19个PKU家系中的15个家系的产前诊断。STR系统的高度多态和孟德尔分离对于日本PKU家系的产前诊断是有用的。

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). More than 100 different mutations have been identified worldwide and it has be revealed that PKU is a highly heterogeneous disorder, I performed the molecular analysis of PKU in East Asia.I have characterized 60% of all PKU alleles in East Asians with 10 PKU mutations. Two major PKU mutations, R413P and IVS4nt-1, may have originated in different populations, spreading in prehistoric times through the Asian continent. I found different mutations between Caucasians and East Asians, and therefore PKU mutations have occurred after racial divergence between Caucasians and East Asians. Furthermore, PKU genotype and in vitro PAH activity in expression analysis correlates to the clinical and biochemical phenotypes in East Asians. The molecular defects at the PAH gene regulate the in vivo PAH activities and clinical manifestations.Illegitimate transcription is useful for the detection of several PKU mutations, since PAH is expressed in the liver only. I identified two missense mutations (R241C,R408Q) by PAH cDNA analysis and characterized a splicing muation caused by a nonsense mutation (Y356X) and a deletion of 10 kb of genomic DNA by analysis of both PAH cDNA and genomic DNA at the PAH locus.As for the DNA polymorphisms, RFLP haplotypes and VNTR were not useful for DNA diagnosis. Short tandem repeat system showed heterozygosity of 70%, which would permit the prenatal diagnosis in 15 of the 19 PKU families. The high degree of polymorphisms and Mendelian segregation in the STR system is useful for the prenatal diagnosis in Japanese families with PKU.