苯丙氨酸羟化酶缺乏症基因型与表型的关系

Correlation between genotype and phenotype in patients with phenylalanine hydroxylase deficiency

目的研究江苏地区苯丙氨酸羟化酶缺乏症（PAHD）患儿的基因突变特点，构建本地区苯丙氨酸羟化酶（PAH）基因突变谱，讨论PAHD基因型与表型的关系。方法应用基因测序技术对70例PAHD患儿及其父母进行PAH基因第1-13外显子及两侧内含子序列分析。结果70例患儿的140个等位基因中125个检测出突变，检出率为89．29％，常见突变依次为EX6—96A〉G（19／125，15．20％），R243Q（18／125，14．40％）和R241C（17／125，13．60％）。经典型苯丙酮尿症（PKU）患儿最常见突变为R243Q和EX6—96A〉G，共占42．86％；中度PKU患儿最常见突变为EX6-96A〉G，R241C和R111X，共占40．74％；轻度PKU患儿最常见的突变是R241C，EX6-96A〉G和R243Q，共占57．89％；轻度HPA患儿最常见的突变是R241C和R243Q，共占40．00％。通过基因型预测的生化表型与患儿实际生化表型一致率为65．63％，其中经典型PKU的预测一致率较高，为81．25％；预测生化表型（即AV值评分）与患儿治疗前血苯丙氨酸水平呈显著负相关（r=-0．77，P〈0．001）。结论江苏地区PAH基因突变谱与其他地区有所不同，基因型与表型之间存在一定的联系。

Objective To explore the characteristics of the phenylalanine hydroxylase （PAH） gene mutations in the patients with phenylalanine hydroxylase deficiency （PAHD） in Jiangsu area, and to analyze the mutational spectrum of PAH and the correlation between genotype and phenotype in patients with PAHD. Methods Totally 70 children with PAHD and their parents were involved in this study. All 13 exons and their flanking intronic sequences ofPAH gene were directly sequenced in these patients. Results 125 different mutations were detected with the relative frequency of 89.29% among 140 allelic genes. The prevalent mutations were EX6-96A〉G （15.20%）, R243Q （14.40%） and R241C （13.60%）. The prevalent mutations in classic phenylketonuria（PKU） were R243Q and EX6-96A〉G （42.86%）. The prevalent muta- tions in moderate PKU were EX6-96A〉G, R241C and R1 l lX （40.74%）. The prevalent mutations in mild PKU were R241C, EX6-96A〉G and R243Q （57.89%）. The prevalent mutations in mild HPA were R241C and R243Q （40.00%）. The consistency between prediction of the biochemical genotype and the observed phenotype was 65.63%, especially in classic PKU （81.25%）. Significant correlations were disclosed between pretreatment levels of phenylalanine and AV sum （r=-0.77, P〈0.001）. Conclusions The frequency distribution of common PAH gene mutation in Jiangsu area was different from the other regions, the genotype of PAHD patients has correlation with the phenotype.