Molecular characterization of phenylketonuria in Japanese patients |
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Authors: | Y Okano Minoru Asada Youngbo Kang Yasuaki Nishi Yutaka Hase Toshiaki Oura Gen Isshiki |
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Institution: | (1) Department of Pediatrics, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8586, Japan e-mail: okano@med.osaka-cu.ac.jp, Tel.: +81 6 645 3816, Fax: +81 6 636 8737, JP;(2) Abeno Public Health Center of Osaka City, Osaka, Japan, JP;(3) Osaka Municipal Rehabilitation Center for the Disabled, Osaka, Japan, JP |
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Abstract: | We characterized phenylalanine hydroxylase (PAH) genotypes of Japanese patients with phenylketonuria (PKU) and hyperphenylalaninemia
(HPA). PKU and HPA mutations in 41 Japanese patients were identified by denaturing gradient gel electrophoresis and direct
sequencing, followed by restriction fragment length polymorphism analysis to find a large deletion involving exons 5 and 6.
Of 82 mutant alleles, 76 (92%) were genotyped showing 21 mutations. The major mutations were R413P (30.5%), R243Q (7.3%),
R241 C (7.3%), IVS4nt-1 (7.3%), T278I (7.3%), E6nt-96A→g (6.1%), Y356X (4.9%), R111X (3.7%), and 442–706delE5/6 (2.4%). Eight
new mutations (L52 S, delS70, S70P, Y77X, IVS3nt-1, A132 V, W187 C, and C265Y) and a polymorphism of IVS10nt-14 were detected.
In vitro PAH activities of mutant PAH cDNA constructs were determined by a COS cell expression system. Six mutations, viz.,
R408Q, L52 S, R241 C, S70P, V388 M, and R243Q, had 55%, 27%, 25%, 20%, 16% and 10% of the in vitro PAH activity of normal
constructs, respectively. The mean pretreatment phenylalanine concentration (0.83±0.21 mmol/l) of patients carrying the R408Q,
R241 C, or L52 S mutation and a null mutation was significantly lower (P<0.0005) than that (1.99±0.65 mmol/l) of patients with both alleles carrying mutations associated with a severe genotype.
Simple linear regression analysis showed a correlation between pretreatment phenylalanine concentrations and predicted PAH
activity in 29 Japanese PKU patients (y=31.9–1.03x, r=0.59, P<0.0001). Genotype determination is useful in the prediction of biochemical and clinical phenotypes in PKU and can be of particular
help in managing patients with this disorder.
Received: 24 July 1998 / Accepted: 12 September 1998 |
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