Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population
Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population
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DOI：
10.1016/j.ymgme.2010.11.158
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发表时间：
2011-02-01
影响因子：
3.8
通讯作者：
Blau, Nenad
中科院分区：
文献类型：
--
作者：
Dobrowolski, Steven F.;Heintz, Caroline;Blau, Nenad
背景：苯丙氨酸羟基酶(PAH)缺陷型苯丙酮尿症(PKU)在土耳其的患病率很高(6500名新生儿中有1例)，但关于该基因的分布和该基因对四氢生物蝶呤(BH4)治疗的影响的数据很少。目的：研究土耳其PKU人群的表型和基因变异特征及其与BH4挑战的生理反应的相关性。方法：我们对462名患者进行了588例高苯丙氨酸血症患者的基因分型和BH4负荷试验(20 mg/kg bw)。根据可获得的体外表达数据计算突变蛋白的剩余多环芳烃活性。结果：共观察到88个突变，其中最常见的错义突变是剪接变异体c.1066-11G>；A(24.6%)。共检测到20个新突变(11个错义突变、4个剪接点突变和5个缺失/插入突变)。588例患者中发现两种突变540例(91.8%)，但在9例不典型的>；患者中发现2种突变(8例顺式突变为p.R155H，另一种突变)，19例患者发现BH4代谢基因突变。最常见的基因型为c.1066-11G>；A/c.1066-11G>；A(15.5%)。大约22%的患者对BH4挑战有反应。相当大的体外残留活性(平均25%的野生型酶)与对BH4的反应有关。在纯合子基因型(n=206)中，表型严重程度(r=0.83)和残留PAH活性(r=0.85)都与BH4应答有关。结论：结合BH4挑战，这些数据使基于基因型的BH4应答分类和证明残留PAH活性的重要性成为可能。这是首次在土耳其PKU患者群体中进行大规模基因分型评估的报告，也记录了严重经典表型的高患病率(47%)。(C)2010 Elsevier Inc.保留所有权利。
Background: The prevalence of phenylalanine hydroxylase (PAH)-deficient phenylketonuria (PKU) in Turkey is high (1 in 6500 births), but data concerning the genotype distribution and impact of the genotype on tetrahydrobiopterin (BH4) therapy are scarce.Objective: To characterize the phenotypic and genotypic variability in the Turkish PKU population and to correlate it with physiological response to BH4 challenge.Methods: We genotyped 588 hyperphenylalaninemic patients and performed a BH4 loading test (20 mg/kg bw) in 462 patients. Residual PAH activity of mutant proteins was calculated from available in vitro expression data. Data were tabulated in the BIOPKU database (www.biopku.org).Results: Eighty-eight mutations were observed, the most common missense mutations being the splice variant c.1066-11G>A (24.6%). Twenty novel mutations were detected (11 missense, 4 splice-site, and 5 deletion/insertions). Two mutations were observed in 540/588 patients (91.8%) but in 9 patients atypical genotypes with >2 mutations were found (8 with p.R155H in cis with another variant) and in 19 patients mutations were found in BH4-metabolizing genes. The most common genotype was c.1066-11G>A/c.1066-11G>A (15.5%). Approximately 22% of patients responded to BH4 challenge. A substantial in vitro residual activity (average >25% of the wild-type enzyme) was associated with response to BH4. In homozygous genotypes (n=206), both severity of the phenotype (r=0.83) and residual PAH activity (r=0.85) correlate with BH4 responsiveness.Conclusion: Together with the BH4 challenge, these data enable the genotype-based classification of BH4 responsiveness and document importance of residual PAH activity. This first report of a large-scale genotype assessment in a population of Turkish PKU patients also documents a high prevalence (47%) of the severe classic phenotype. (C) 2010 Elsevier Inc. All rights reserved.