Okano Y, Eisensmith R C, Güttler F, Lichter-Konecki U, Konecki D S, Trefz F K, Dasovich M, Wang T, Henriksen K, Lou H
Howard Hughes Medical Institute, Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030.
N Engl J Med. 1991 May 2;324(18):1232-8. doi: 10.1056/NEJM199105023241802.
Phenylketonuria is a metabolic disorder that results from a deficiency of the hepatic enzyme phenylalanine hydroxylase. Its clinical phenotype varies widely, and to date more than 10 mutations in the phenylalanine hydroxylase gene have been identified in persons with the disorder. We attempted to relate the clinical phenotype of patients to their genotype.
We studied 258 patients with phenylketonuria from Denmark and Germany for the presence of eight mutations previously found in patients from these countries. The in vitro activity of the enzymes associated with these mutations was determined by expression analysis in heterologous mammalian cells. The level of activity was then used to predict the in vivo level of phenylalanine hydroxylase activity in patients with various combinations of mutant phenylalanine hydroxylase alleles.
The eight mutations involved 64 percent of all mutant phenylalanine hydroxylase alleles in the patients. Expression analysis showed that these mutant enzymes produced from 0 to 50 percent of normal enzyme activity. The predicted level of phenylalanine hydroxylase activity correlated strongly with the pretreatment serum level of phenylalanine (r = 0.91, P less than 0.001 in the Danish patients and r = 0.74, P less than 0.001 in the German patients), phenylalanine tolerance in the Danish patients (r = 0.84, P less than 0.001), and the serum phenylalanine level measured after standardized oral protein loading in the German patients (r = 0.84, P less than 0.001).
Our results strongly support the hypothesis that there is a molecular basis for phenotypic heterogeneity in phenylketonuria. The establishment of genotype will therefore aid in the prediction of biochemical and clinical phenotypes in patients with this disease.
苯丙酮尿症是一种由于肝脏苯丙氨酸羟化酶缺乏导致的代谢紊乱疾病。其临床表型差异很大，迄今为止，已在患有该疾病的患者中鉴定出苯丙氨酸羟化酶基因的10多种突变。我们试图将患者的临床表型与其基因型联系起来。
我们研究了来自丹麦和德国的258例苯丙酮尿症患者，以确定先前在这些国家的患者中发现的8种突变的存在情况。通过在异源哺乳动物细胞中的表达分析来确定与这些突变相关的酶的体外活性。然后使用活性水平来预测具有突变型苯丙氨酸羟化酶等位基因各种组合的患者体内苯丙氨酸羟化酶活性水平。
这8种突变涉及患者中所有突变型苯丙氨酸羟化酶等位基因的64%。表达分析表明，这些突变酶产生的正常酶活性为0%至50%。预测的苯丙氨酸羟化酶活性水平与丹麦患者的治疗前血清苯丙氨酸水平密切相关（r = 0.91，P < 0.001），与丹麦患者的苯丙氨酸耐受性密切相关（r = 0.84，P < 0.001），以及与德国患者标准化口服蛋白质负荷后测量的血清苯丙氨酸水平密切相关（r = 0.84，P < 0.001）。
我们的结果有力地支持了苯丙酮尿症表型异质性存在分子基础这一假设。因此，基因型的确定将有助于预测该疾病患者的生化和临床表型。
