吉林和辽宁地区80例苯丙酮尿症患儿苯丙氨酸羟化酶基因突变分析

Mutations of phenylalanine hydroxylase gene in patients with phenylketonuria in Jilin and Liaoning Province

背景苯丙酮尿症(phenylketonuria,PKU)是一种常染色体隐性遗传的氨基酸代谢病,由苯丙氨酸羟化酶(phenylalanine hydroxylase,PAH)活性的部分或完全缺失引起,会使苯丙氨酸在体内蓄积,导致患儿出现神经系统等损害。PAH基因突变种类和频率存在明显的地域和种族差异。目的分析吉林和辽宁地区苯丙酮尿症80例患儿苯丙氨酸羟化酶PAH基因的突变特征。方法对2016-2018年吉林辽宁两省医院80例PKU患儿PAH基因的13个外显子及其侧翼序列,包含5’和3’端非编码区,进行一代测序点突变分析。结果80例患儿共检出161个突变位点,占292个突变等位基因的55.14%。其中,R243Q占比最高(15.75%),IVS11-3 A>T、R413P、IVS4-1 G>A和EX6-96A>G次之,占比依次为4.11%、3.42%、3.08%和3.08%。另外5个低频突变位点Y356^(*)、R111^(*)、R241C、R53H a和IVS2+19 T>C突变频率为1%~3%。此次,我们发现PAH基因1个新的突变点F294S,位于8号外显子。结论依据此次吉林辽宁地区80例PKU患儿PAH基因的突变特点,为该地区预防PKU出生缺陷提供理论依据。

Background Phenylketonuria(PKU)is one of the most common inherited inborn errors of metabolism caused by the deficiency of phenylalanine hydroxylase(PAH),and then impairs postnatal cognitive development.The incidence of various PAH variations differs by race and ethnicity.Objective To investigate the characteristics of PAH gene mutations in children with PKU in Jilin and Liaoning province.Methods From 2016 to 2018,80 PKU patients and their families were recruited for this study in the hospitals of Jilin and Liaoning province.Patients were sequentially screened for single-base variants within PAH via direct Sanger sequencing,and 13 exons of PAH gene and their flanking sequences(5’and 3’non-coding regions)were included by the sequencing.Results Of the 292 mutant alleles,161 mutations were detected in all patients,with the detection rate of 55.14%.In addition,R243Q was the most prevalent mutation(the frequency was 15.75%)in terms of mutation frequency.Other mutations with relatively high frequencies were IVS11-3 A>T,R413P,IVS4-1 G>A and EX6-96A>G(4.11%,3.42%,3.08%,3.08%,respectively).Five mutations,including Y356^(*),R111^(*),R241C,R53H and IVS2+19 T>C were found with relatively lower frequencies(ranging from 1%to 3%).We also found the novel F294S mutation in exon 8.Conclusion This study shows the results of mutations in the PAH gene of the 80 children with PKU in Jilin and Liaoning province,which may provide references for reducing the incidence of PKU in these provinces.