Desviat L R, Pérez B, Gámez A, Sánchez A, García M J, Martínez-Pardo M, Marchante C, Bóveda D, Baldellou A, Arena J, Sanjurjo P, Fernández A, Cabello M L, Ugarte M
Centro de Biología Molecular Severo Ochoa CSIC-UAM, Universidad Autónoma, Madrid, Spain.
Eur J Hum Genet. 1999 Apr;7(3):386-92. doi: 10.1038/sj.ejhg.5200312.
We present an extensive study of the genetic diversity of phenylalanine hydroxylase deficiency in the Spanish phenylketonuria population. We have analysed 195 PKU patients by DGGE analysis identifying 67 different mutations which represent 89% of the total mutant chromosomes. Seventeen mutations first described in Spain have not yet been detected elsewhere; ten of these are reported here for the first time. The clinical significance of this high genetic heterogeneity was examined by analysing the genotype-phenotype correlations, mainly focusing on the mild hyperphenylalaninaemia (MHP) phenotype. The genotypes found in a group of 93 MHP patients, the largest analysed so far, are described in detail, as well as the relative frequencies of the MHP mutations identified. From the total pool of mutations, 27 can be considered severe, 18 can be defined as mild and 13 as associated with MHP. The prevalent mutations correspond to one severe mutation (IVS10nt-11), one MHP mutation (A403V) and two mild mutations (165T and V388M). The high frequency of mutations with a low degree of severity can explain the relatively higher prevalence of MHP and mild PKU phenotypes in Spain compared with NOrthern European populations. We have looked at the geographical distribution in Spain of the more common mutations, finding evidence of local mutation clustering, which could be the result of differences in the ethnic background and/or of genetic drift within each region.
我们对西班牙苯丙酮尿症患者群体中苯丙氨酸羟化酶缺乏症的基因多样性进行了广泛研究。我们通过变性梯度凝胶电泳（DGGE）分析了195例苯丙酮尿症患者，鉴定出67种不同突变，这些突变占突变染色体总数的89%。17种首次在西班牙发现的突变在其他地方尚未被检测到；其中10种在此首次报道。通过分析基因型与表型的相关性，主要关注轻度高苯丙氨酸血症（MHP）表型，研究了这种高度基因异质性的临床意义。详细描述了在一组93例MHP患者（迄今为止分析的最大群体）中发现的基因型，以及所鉴定的MHP突变的相对频率。在所有突变中，27种可被视为严重突变，18种可定义为轻度突变，13种与MHP相关。常见突变包括一种严重突变（IVS10nt-11）、一种MHP突变（A403V）和两种轻度突变（165T和V388M）。与北欧人群相比，低严重程度突变的高频率可以解释西班牙MHP和轻度苯丙酮尿症表型相对较高的患病率。我们研究了西班牙较常见突变的地理分布，发现了局部突变聚集的证据，这可能是由于各地区种族背景差异和/或基因漂变所致。
