Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Metab Brain Dis. 2017 Oct;32(5):1685-1691. doi: 10.1007/s11011-017-0048-7. Epub 2017 Jul 4.
Phenylketonuria (PKU), one of the most common inborn errors of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene (PAH). PKU has wide allelic heterogeneity, and over 600 different disease-causing mutations in PAH have been detected to date. Up to now, there have been no reports on the minihaplotype (VNTR/STR) analysis of PAH locus in the Iranian population. The aims of the present study were to determine PAH mutations and minihaplotypes in Iranian families with PAH deficiency and to investigate the correlation between them. A total of 81 Iranian families with PAH deficiency were examined using PCR-sequencing of all 13 PAH exons and their flanking intron regions to identify sequence variations. Fragment analysis of the PAH minihaplotypes was performed by capillary electrophoresis for 59 families. In our study, 33 different mutations were found accounting for 95% of the total mutant alleles. The majority of these mutations (72%) were distributed across exons 7, 11, 2 and their flanking intronic regions. Mutation c.1066-11G > A was the most common with a frequency of 20.37%. The less frequent mutations, p.Arg261Gln (8%), p.Arg243Ter (7.4%), p.Leu48Ser (7.4%), p.Lys363Asnfs*37 (6.79%), c.969 + 5G > A (6.17%), p.Pro281Leu (5.56), c.168 + 5G > C (5.56), and p.Arg261Ter (4.94) together comprised about 52% of all mutant alleles. In this study, a total of seventeen PAH gene minihaplotypes were detected, six of which associated exclusively with particular mutations. Our findings indicate a broad PAH mutation spectrum in the Iranian population, which is consistent with previous studies reporting a wide range of PAH mutations, most likely due to ethnic heterogeneity. High prevalence of c.1066-11G > A mutation linked to minihaplotype 7/250 among both Iranian and Mediterranean populations is indicative of historical and geographical links between them. Also, strong association between particular mutations and minihaplotypes could be useful for prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) in affected families.
苯丙酮尿症（PKU）是最常见的氨基酸代谢遗传缺陷之一，由苯丙氨酸羟化酶（PAH）基因（PAH）的突变引起。PKU 具有广泛的等位基因异质性，迄今为止已检测到超过 600 种不同的致病性 PAH 突变。目前，还没有关于伊朗人群中 PAH 基因座的微卫星（VNTR/STR）分析的报道。本研究的目的是确定伊朗 PAH 缺乏症家系中 PAH 的突变和微卫星，并探讨它们之间的相关性。使用所有 13 个 PAH 外显子及其侧翼内含子区域的 PCR 测序，对 81 个伊朗 PAH 缺乏症家系进行了检测，以鉴定序列变异。对 59 个家系的 PAH 微卫星进行毛细管电泳片段分析。在我们的研究中，发现了 33 种不同的突变，占总突变等位基因的 95%。这些突变中的大多数（72%）分布在 7、11 和 2 号外显子及其侧翼内含子区域。突变 c.1066-11G>A 是最常见的，频率为 20.37%。较少见的突变包括 p.Arg261Gln（8%）、p.Arg243Ter（7.4%）、p.Leu48Ser（7.4%）、p.Lys363Asnfs*37（6.79%）、c.969+5G>A（6.17%）、p.Pro281Leu（5.56%）、c.168+5G>C（5.56%）和 p.Arg261Ter（4.94%），这些突变一起构成了所有突变等位基因的约 52%。在本研究中，共检测到 17 种 PAH 基因微卫星，其中 6 种与特定突变密切相关。我们的研究结果表明，伊朗人群中存在广泛的 PAH 突变谱，与先前报道的 PAH 突变范围广泛的研究结果一致，这很可能是由于种族异质性所致。伊朗和地中海人群中 c.1066-11G>A 突变与微卫星 7/250 之间的高相关性表明了它们之间的历史和地理联系。此外，特定突变与微卫星之间的强关联可用于受影响家系的产前诊断（PND）和植入前遗传学诊断（PGD）。
