부산대학교 도서관

Different mutations in the phenylalanine hydroxylase (PAH) gene appear to correlate with variations in the biochemical and clinical features of patients with phenylketonuria (PKU) and hyperphenylalaninemia (HPA). The buildup of phenylalanine that occurs in PKU and HPA usually results from a deficiency in the activity of the PAH enzyme. Researchers analyzed DNA samples taken from 35 patients with PKU or HPA and 1 carrier and identified a variety of mutations in the PAH gene, 5 of which were new. For 32 patients whose PAH genes were fully characterized, there was a strong association between the patients' phenylalanine levels and predictions of their PAH activity based on previous laboratory studies of the corresponding mutant PAH enzymes. A strong association was also found between the predicted PAH activity and the patients' tolerance for phenylalanine. The findings indicate that PAH genetic screening may be useful even in the variable American population from which the study participants were selected.
Objective. To determine the molecular basis of phenylketonuria (PKU) and related hyperphenylalaninemia (HPA) and to establish correlations between phenylalanine hydroxylase (PAH) genotypes and biochemical and clinical phenotypes in an ethnically diverse US population, PAH genotypes were determined in 35 patients with PKU or HPA and 1 carrier from the Medical Genetics Clinic of the Emory University School of Medicine. Methodology. Patients were identified through Georgia's population-based newborn screening program. PAH genotypes in these individuals were determined from dried blood spots or whole-blood samples using a combination of polymerase chain reaction-mediated amplification, denaturing gradient gel electrophoresis, and direct-sequence analysis. The phenotypic severity of patients with PKU and HPA was based on pretreatment serum phenylalanine (PHE) levels during the neonatal period and on dietary tolerance of PHE later in life. Results. Sixty-eight (96%) of 71 mutant alleles were identified. Major mutations in this population included R408W (11 of 71), 165T (11 of 71), Y414C (6 of 71), L348V (4 of 71), and IVS10 (4 of 71). Five new nucleotide substitutions, E76A (1 of 71), R241L (1 of 71), Q304R (2 of 71), C334S (1 of 71), and R400R (2 of 71) were also detected. Thirty-two of the thirty-five nonrelated patients examined in this study were completely genotyped. Strong correlations were observed between the level of PAH activity predicted from the genotype, when known from previous in vitro expression studies of the mutant proteins, and pretreatment serum PHE levels (r = .841) or clinical severity (Kendall rank-order correlation coefficient, .936). Conclusions. These results demonstrate strong correlations between PAH genotype and biochemical and clinical phenotypes in this heterogeneous American sample population, extending our previous findings from relatively homogeneous European populations. These correlations further demonstrate the clinical utility of genotype analysis in the treatment of patients with PKU and HPA. Pediatrics 1996;97:512-516, phenylketonuria, hyperphenylalaninemia, phenylalanine hydroxylase, mutation, genotype-phenotype correlation.
ABBREVIATIONS. PKU, phenylketonuria; PAH, phenylalanine hydroxylase; VNTR, variable number of tandem repeat; HPA, hyperphenylalaninemia; PHE, phenylalanine; PCR, polymerase chain reaction; DGGE, denaturing gradient gel electrophoresis. Phenylketonuria (PKU; McKusick's Mendelian inheritance [...]