Netzer Christian, Todt Unda, Heinze Axel, Freudenberg Jan, Zumbroich Vera, Becker Tim, Goebel Ingrid, Ohlraun Stephanie, Goebel Hartmut, Kubisch Christian
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141B(3):257-60. doi: 10.1002/ajmg.b.30283.
Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case-control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype-tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender-matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single-marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht-SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA.
ATP1A2基因的突变会导致2型家族性偏瘫性偏头痛（FHM），这是一种罕见的伴有先兆的偏头痛（MA）单基因形式。此外，在单个家系中常见偏头痛形式的家族聚集现象中发现了罕见的ATP1A2错义变异。为了确定常见的ATP1A2多态性是否也对MA的发病机制有影响，我们对284例MA患者和241名对照个体进行了系统的病例对照关联研究。通过对45例MA患者的23个编码外显子和相邻内含子区域进行直接测序，鉴定出16种多态性（12个单核苷酸多态性、3个小插入缺失、1个微卫星标记）。测序结果用于估计7种常见的ATP1A2单倍型（频率>5%），覆盖该区域单倍型多样性的约97%。随后，对95名有MA家族史的个体、189名散发型MA个体以及性别匹配的对照样本进行了6个单倍型标签单核苷酸多态性/多态性的基因分型。使用FAMHAP程序进行单倍型分析。在MA患者（或患者亚组）和对照组之间未检测到ATP1A2单倍型分布的显著差异。在单标记分析中，比较了病例组和对照组之间ATP1A2多态性的等位基因和基因型频率。6个单倍型标签单核苷酸多态性和微卫星标记的任何一个等位基因均与MA无显著关联。总之，我们没有发现证据表明ATP1A2对复杂遗传型MA的发病机制有共同作用。
