Carter K C, Byck S, Waters P J, Richards B, Nowacki P M, Laframboise R, Lambert M, Treacy E, Scriver C R
DeBelle Laboratory, McGill University-Montreal Children's Hospital Research Institute, Quebec, Canada.
Eur J Hum Genet. 1998 Jan;6(1):61-70. doi: 10.1038/sj.ejhg.5200153.
We describe variation at the PAH locus in the population of Quebec. We successfully analyzed 135 of 141 chromosomes from phenylketonuria (PKU) probands (95.7% of the sample), and eight additional chromosomes from a small number of probands with non-PKU hyperphenylalaninemia (HPA). The full set of chromosomes harboured 45 different PAH mutations: i) seven polymorphisms (IVS2nt19, IVS3nt-22, IVS6nt-55, Q232Q, V245V, L385L, Y414Y); ii) four mutations causing non-PKU HPA (T92I, E390G, R408Q, D415N); iii) 34 mutations causing PKU. Only six mutations (M1V, R261Q, F299C, S349P, R408W and IVS12nt1) occurred in the whole province at relative frequencies > 5%: most are rare and probably identical by descent. By studying associations of mutations with polymorphic haplotype alleles, we found examples of mutations on different haplotypes that were identical by state, but not by descent because they were recurrent mutations (E280K and R408W); and examples of mutations identical both by state and by descent because of intragenic recombination (S67P, G218V, V245A and IVS12nt1). Ten mutations were first described in Quebec and five are still unique there; three of these 'Quebec' mutations are reported here for the first time (c.125A-->T (K42I); [c.470G-->A; c.471A--C] (R157N); c.707nt-55 (IVS6nt-55). The PAH mutations stratify by geographic region and population, their distributions validating hypotheses about European range expansion to North America during three separate phases of immigration and demographic expansion in the Quebec region over the past four centuries. The PAH homozygosity value (j) is 0.06 for the total Quebec sample (0.5-0.08 by regions), and the corresponding homoallelic fraction of mutant PAH genotypes is 24%. These findings are a documentation of genetic diversity in the Quebec population.
我们描述了魁北克人群中苯丙氨酸羟化酶（PAH）基因座的变异情况。我们成功分析了141名苯丙酮尿症（PKU）先证者中的135条染色体（占样本的95.7%），以及少数非PKU高苯丙氨酸血症（HPA）先证者的另外8条染色体。整套染色体包含45种不同的PAH突变：i）7种多态性（IVS2nt19、IVS3nt - 22、IVS6nt - 55、Q232Q、V245V、L385L、Y414Y）；ii）4种导致非PKU HPA的突变（T92I、E390G、R408Q、D415N）；iii）34种导致PKU的突变。在全省范围内，只有6种突变（M1V、R261Q、F299C、S349P、R408W和IVS12nt1）的相对频率>5%：大多数是罕见的，可能是同源的。通过研究突变与多态性单倍型等位基因的关联，我们发现了不同单倍型上状态相同但并非同源的突变实例，因为它们是复发性突变（E280K和R408W）；以及由于基因内重组导致状态和同源性均相同的突变实例（S67P、G218V、V245A和IVS12nt1）。10种突变首次在魁北克被描述，5种在那里仍然是独特的；其中3种“魁北克”突变在此首次报道（c.125A→T（K42I）；[c.470G→A；c.471A→C]（R157N）；c.707nt - 55（IVS6nt - 55）。PAH突变按地理区域和人群分层，其分布验证了关于在过去四个世纪魁北克地区三个不同的移民和人口扩张阶段欧洲向北美范围扩张的假设。魁北克总样本的PAH纯合度值（j）为0.06（各地区为0.5 - 0.08），突变PAH基因型的相应同型等位基因比例为24%。这些发现记录了魁北克人群的遗传多样性。
