西北五省区苯丙酮尿症患者苯丙氨酸羟化酶基因外显子12突变分析

Mutation analysis in exon 12 of the PAH gene in phenylketonuria patients of Northwest China

目的研究分析西北五省区苯丙酮尿症患者苯丙氨酸羟化酶（PAH）基因外显子12的突变特征，为该地区苯丙酮尿症（PKU）的产前诊断和遗传咨询提供理论依据。方法应用PCR产物直接测序法对276例PKU患儿及其父母的PAH基因启动子、第1～13外显予及其旁侧内含子区域进行基因突变分析。结果（1）PAH基因外显子12中突变基因检出率为7．4％，共检出8种PAH基因突变，其中，错义突变7种、无义突变1种，最常见的突变是R413P（4．0％）；（2）PAH基因外显子12突变检出率由高到低依次为宁夏（11．3％）、陕西（9．7％）、甘肃（5．2％）、新疆（3．3％）和青海（3．1％），R413P突变在新疆、宁夏、陕西和甘肃四省区中突变检出率分别为2．5％、5．3％、5．6％和5．2％，Y414X（0．7％）和L430P（2．7％）仅在宁夏检出，R408W（1．0％）仅在青海检出；（3）R413P是西北及等国内大多数地区PAH基因外显子12最为常见的突变，R413P突变在西北地区中的检出率低于山西、河南、河北、天津、沈阳、云南等大多数国内省区，日本R413P、台湾R408Q突变和挪威、瑞典、北爱尔兰及苏格兰的R408W突变的检出率显著高于西北地区。西北五省区检出的Y414X、Q419R和L430P三种突变在我国其它地区尚未见报道。结论（1）西北地区PAH基因外显子12突变以R413P为主，与韩国、日本相似，但不同于挪威、瑞典等欧洲国家以R408W为主。推测R413P突变基因频率的高处在日本，R408Q1和R408W突变基因频率的高处分别在台湾、欧洲。（2）西北五省区PAH基因外显子12突变特点有别于中国其他地区和部分欧洲国家，表现出多民族聚居地区基因突变特有的多样性和复杂性。

Objective： To investigate the mutation characteristics in exon 12 of the phenylalanine hydroxylase （PAH） gene in phenylketonuria （PKU） patients of Northwest China, in order to provide basic information for genetic counseling and prenatal diagnosis. Methods： Mutations of the PAH gene were detected in promoter, exons 1-13 with flanking introns of PAH gene by PCR and DNA sequencing in 276 families with PKU. Results： （1）The frequency of mutation alleles in exon 12 of PAH gene was 7.4%.A total of 8 different mutations were detected, including missense （n=7） and nonsense （n=1） .The mutation R413P was identified with relative higher frequencies of 4.8%.（2）The frequency of mutation alleles in Ningxia, Shaanxi, Gansu, Xinjiang and Qinghai were 11.3%, 9.7%, 5.2%, 3.3% and 4.8%, respectively.Furthermore, the Y356X mutation was novel in Xinjiang （4.1%） , Ningxia （3.3%） and Qinghaiz （3.1%） .Moreover, the frequencies of the novel R413P mutation in Xinjiang, Ningxia, Shaanxi and Gansu were 2.5%, 5.3%, 5.6% and 5.2%, respectively,Y414X and L430P were only detected in Niaxia province and R408W was merely detected in Qinhai province.（3）R413P was the most prevalentmutiaton form in Northwest and most provinces of China. The frequnencies of R413P mutation in Northwest were significantly lower than those of the most provinces such as Shanxi, Henan, Hebei, Tianjin, Shenyang, Yunnan, etc.In addition, the frequnencies of R413P and R408Q in Northwest China were significantly lower than those of Japan, Taiwan, respectively.Moreever, the frequencies of R408W in Norway, Sweden, Northern Ireland and Scotland were higher than that of in Northwest China.Consult literature at home and abroad, Y414X, Q419R and L430P have not been reported in southern China. Conclusion： （1） Similar to Korea, and Japan, R413P was the common mutation in exon 12 of PAH gene in PKU patients from Northwest China different from that Norway, Sweden and other European countries were given priority to with R408W mutation.The region with higher frequency of mutation R413P was Japan and the region with higher frequency of mutation R408Q and R408W were Taiwan, Europe, respectively.（2）According to the research, the types and characteristics of the gene mutation in exon 12 of PAH gene in Northwest have been different from other areas in China and a lot of European countries.The gene mutation in this area shows their diversity, complexity and has significant ethnic uniqueness.