经典型苯丙酮尿症患者的致病基因突变分析

国际医药卫生导报　２０１８年　第２４卷　第１０期　ＩＭＨＧＮ，Ｍａｙ ２０１８，Ｖｏｌ．２４　Ｎｏ．　１０

苯丙酮尿症（ｐｈｅｎｙｌｋｅｔｏｎｕｒｉａ，ＰＫＵ）是一种以智力发育不全为主要特征的常染色体隐性遗传病，由于苯丙氨酸羟化酶（ｐｈｅｎｙｌａｌａｎｉｎｅ　ｈｙｄｒｏｘｙｌａｓｅ，ＰＡＨ）基因突变导致肝脏苯丙氨酸羟化酶合成障碍，致使苯丙氨酸（ｐｈｅｎｙｌａｌａｎｉｎｅ，Ｐｈｅ）代谢异常所致，我国的群体发病率为１／１１　１４４［１］。１９８３年Ｗｏｏ　等［２］成功分离和克隆了ＰＡＨ基因，为ＰＫＵ的基因诊断和产前诊断奠定了基础，截至２０１４年，国内外相关

经典型苯丙酮尿症患者的致病基因突变分析

植瑞东　何夏怡　赵思婷　吴文奇　宁红珠

５２６０２０　肇庆医学高等专科学校

通信作者：何夏怡，Ｅ－ｍａｉｌ：２５３４７０７３３０＠ｑｑ．ｃｏｍ

ＤＯＩ：１０．３７６０／ｃｍａ．ｊ．ｉｓｓｎ．１００７－１２４５．２０１８．１０．０１５

【摘要】　目的　分析经典型苯丙酮尿症患者的苯丙氨酸羟化酶致病基因的突变类型，为本病患者的基因诊断和产前诊断提供科学的理论依据。方法　随机收集３６例确诊为经典型苯丙酮尿症的患者为实验组，３６名无血缘关系的正常成员为对照组，应用ＰＣＲ直接测序法分别对实验组和对照组的苯丙氨酸羟化酶基因进行检测分析。结果　在实验组３６例患者的苯丙氨酸羟化酶基因的１３个外显子中，共检出６３个突变基因，分属２１种类型，总检出率为８７．５０％。其中突变频率最高的基因为Ｒ２４３Ｑ（２７．７８％），其次为ＥＸ６－９６Ａ＞Ｇ（１１．１１％）、Ｒ４１３Ｐ（５．５６％）、Ｒ１１１Ｘ（４．１７％）、Ｒ２６１Ｑ（４．１７％）、Ｙ３５６Ｘ（４．１７％）和Ｖ３９９Ｖ（４．１７％）。突变位点分布在第３、５、６、７、９、１０、１１、１２外显子，其中第７外显子发生的突变最多（４０．２８％），其次为第６外显子（１３．８９％）、第１１外显子（１１．１１％）和第１２外显子（８．３３％）。此外，测序结果还显示第１２外显子发生了Ｄ４１５Ｙ错义突变，对照组未见此突变，经查阅国际ＰＡＨ基因突变数据库，未见Ｄ４１５Ｙ突变的相关报道。结论　广东省肇庆地区经典型ＰＫＵ患者的热点突变基因为Ｒ２４３Ｑ、ＥＸ６－９６Ａ＞Ｇ、Ｒ４１３Ｐ、Ｒ１１１Ｘ、Ｒ２６１Ｑ、Ｙ３５６Ｘ和Ｖ３９９Ｖ，突变区域主要分布在第６、７、１１、１２外显子。此外，在第１２外显子发现了Ｄ４１５Ｙ新突变，此发现丰富了中国人群的ＰＡＨ基因突变谱。

【关键词】　苯丙酮尿症；苯丙氨酸羟化酶；致病基因；分析

Sudden changing of pathogenic genes in patients with phenylketonuria Zhi Ruidong, He Xiayi, Zhao Siqi, Wu Wenqi, Ning Hongzhu

Zhaoqing Medical College, Zhaoqing 526020, China

Corresponding author: He Xiayi, E-mail: 2534707330@

【Abstract】Objective To analyze the types of phenylalanine hydroxylase which are the pathogenic genes in patients with phenylketonuria and provide a science theoretical basis for the disease diagnosis and prenatal diagnosis. Methods 36 patients with phenylketonuria were randomly selected as a test group and 36 unrelated normal members a control group. The phenylalanine hydroxylase genes in both groups were detected using PCR method and were analyzed. Results 13 expressed regions were found with phenylalanine hydroxylase genes in teh test group; and 63 mutant genes had been confirmed and belonged to 21 different types. The total detection rate was 87.5%; among which, R243Q（27.78%）had highest mutant frequency, and followed by EX6-96A＞G(11.11%), R413P(5.56%), R111X(4.17%), R261Q(4.17%), Y356X(4.17%), and V399V(4.17%). The mutation sites appeared in the 3rd, 5th, 6th, 7th, 9th, 10th, 11th, and 12th expressed regions; among which, the 7th (40.28%) changed most, and followed by the 6th (13.89%), 11th (11.11%), and 12th (8.33%). What’s more, the test results showed that the 12th expressed gene occurred a D415Y Messene mutation, which was not found in the control group and this result wass also not recorded in International PAH gene mutation database. Conclusions Zhaoqing, Guandong province is a place in which patients with phenylketonuria can be easily found with mutant genes marked R243Q, EX6-96A＞G, R413P, R111X, R261Q, Y356X, and V399V. The mutation sites mainly appear in the 3rd, 5th, 6th, 7th, 9th, 10th, 11th, and 12th expressed regions. Besides, a D415Y Messene mutation was found in the 12th gene, which has enriched the PAH gene mutation spectrum.

【Key words】 Phenylketonuria; Phenylalanine hydroxylase; Pathogenic genes; Analysis

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