苯丙氨酸羟化酶突变基因型与生化表型分析  

Correlation between genotypes and biochemical phenotypes of phenylalanine hydroxylase in patients with phenylketonuria

作　　者：舒剑波[1] 孟英韬[1] 党利亨[1] 付伯津 宋力[1] 

机构地区：[1]天津市儿童医院、天津市儿科研究所,300074 [2]天津市妇女儿童保健中心

出　　处：《中华医学遗传学杂志》2012年第6期635-641,共7页Chinese Journal of Medical Genetics

摘　　要：目的探讨苯丙酮尿症（phenylketonuria，PKU）患者苯丙氨酸羟化酶基因（phenylalanine hydroxylase，PAH）突变基因型与生化代谢表型的相关性。方法用聚合酶链式反应一单链构象多态性、变性高效液相色谱分析和DNA测序法对102例治疗前血清苯丙氨酸（phenylalanine，Phe）高于120μmol／L患儿基因组DNA进行PAH基因分析，观察突变基因型与生化代谢表型的相关性。结果（1）生化代谢表型为经典型PKU（Phe〉1200btmol／L）69例，中度PKU（Phe600～1200μmol／L）31例，轻度PKU（Phe400～600μmol／L）2例。（2）共检出基因突变41种，基因型75种。（3）纯合突变基因型共9例（8．8％），含R111X／R111X基因型3例，IVS4-1G〉A／IVS4—1G〉A基因型1例，R243Q／R243Q基因型3例和V399V／V399V基因型2例。9例纯合突变中除1例R243Q／R243Q基因型患者的生化代谢表型属中度PKU外，其余8例生化代谢表型均属经典型苯丙酮尿症。（4）复合突变基因型共91例（89．2％），生化代谢表型属经典型苯丙酮尿症的61例、中度PKU的29例和轻度PKU的1例。（5）复合突变基因型R11IX／R243Q和EX6—96A〉G（Y204C）／R243Q均可见于经典型苯丙酮尿症和中度PKU生化代谢表型；均属于无效突变等位基因的R111X／V399V基因型、EX6—96A〉G／Y356X和EX6—96A〉G／V399V生化代谢表型为中度PKU。含不同无效突变相同错义突变的R111X／A165D和R176X／A165D基因型分别表现为中度PKU和经典型苯丙酮尿症表型。结论本研究中多数患者的突变基因型属复合突变。因突变等位基因的自由组合，使患者的基因型和生化表型之间关系复杂化。虽然大多数突变基因型与生化表型相关，但仍有个别与规律不一致的现象。因此，在PKU的遗传咨询中，依据患者的突变基因型分析评估预后要慎重。同样的基因型，患者表现出不同的生化代谢表型的现象，提示在苯丙氨酸的�Objective To investigate the correlation between genotypes and biochemical phenotypes of phenylalanine hydroxylase （PAH） in patients with phenylketonuria （PKU）. Methods Thirteen exons and flanking introns of PAH gene in 102 patients with high blood phenylalanine levels （Phe〉120μmol/L） at initial diagnosis were amplified with polymerase chain reaction and analyzed with single strand conformation polymorphism （SSCP）, denaturing high performance liquid chromatography （DHPLC） and DNA sequencing. Correlation between genotypes and biochemical phenotypes was analyzed. Results Biochemical assaying has indicated that 69 patients had classical PKU （Phe〉1200 μmol/L）, 31 were moderate （Phe 600-1200 μmol/L）, and 2 were mild （Phe 400-600 μmol/L）. More than 41 mutations and 75 genotypes have been identified. There were 9 （8.8 % ） homozygous mutations, which included 3 eases with Rl11X/R111X, 1 ease with IVS4-1G〉 A/IVS4-1G〉 A, 3 eases with R243Q/R243Q and 2 eases with V399V/V399V. Among these 8 belonged to classic PKU phenotypes, except for a R243Q/R243Q genotype which has led to a moderate phenotype. In 91 patients carrying compound PAH mutations, 61 were classic, 29 were moderate, and 1 was mild. Patients who were heterozygous for R111X/R243Q and EX6-96A〉G（Y204C）/R243Q were found with both classic and moderate PKU phenotypes. Certain individuals who have carried 2 null mutant alleles such as RlllX/V399V, EX6-96A〉G/Y356X and EX6-96A〉G/V399V only showed a moderate phenotype. Individuals with RlllX/A165D and R176X/A165D genotypes, on the other hand, respectively presented moderate and classic PKU phenotypes. Conclusions Ninety percent of our patients are compound heterozygotes. Independent assortment of mutant alleles has resulted in a complex genotype- phenotype correlation. Although in most cases a correlation may be found, caution should still be taken upon genetic counseling. The phenomena where similar or even identical genotype may give rise to different biochemical

关 键 词：苯丙酮尿症 苯丙氨酸羟化酶 基因型 生化表型 

分 类 号：R714.5[医药卫生—妇产科学]