Linkage analysis of a Japanese family with autosomal dominant Parkinsonism

我们进行了全基因组连锁分析的一个日本家庭与常染色体显性帕金森氏症，其表现出的临床特征与常见的帕金森氏病兼容。参数两点连锁分析在D12 S345（12p11.21）产生最高LOD评分4.32。围绕该标记的13.6 cM间隔的参数多点连锁分析产生的LOD评分几乎一致高于4.0，在D12 S85（12 q12）的Zmax为4.71。单倍型分析在D12 S1631和D12 S339处检测到两个专性重组事件，并在12p11.2-q13.1的13.6 cM间隔内定义了疾病相关单倍型。该单倍型为所有患者和一些未受影响的携带者所共有，表明该疾病在该家族中的渗透是不完全的。这种低表达率表明环境或其他遗传因素改变了疾病的表达。非参数两点和多点连锁分析，这是独立的，在D12 S345产生的Zmax LOD得分分别为14.2和24.9，强烈支持帕金森氏症基因座在这个家庭的映射到12p11.23-q13.11。这个染色体区域不同于任何已知的遗传性帕金森病的基因座，与这个家族中帕金森病的独特遗传特征保持一致。命名为PARK 8。

We performed genome-wide linkage analysis of a Japanese family with autosomal-dominant parkinsonism, which exhibits clinical features compatible with those of common Parkinson's disease. Parametric two-point linkage analysis yielded a highest LOD score of 4.32 at D12S345 (12p11.21). Parametric multipoint linkage analysis of the 13.6 cM interval around this marker yielded LOD scores almost uniformly higher than 4.0 with a Zmax of 4.71 at D12S85 (12q12). Haplotype analysis detected two obligate recombination events at D12S 1631 and D12S339 and defined the disease-associated haplotype in the 13.6 cM interval in 12p11.2-q13.1. This haplotype was shared by all the patients and some unaffected carriers, suggesting that the disease penetration in this family is incomplete. This low penetrance suggests that environmental or other genetic factors modify expression of the disease. Nonparametric two-point and multipoint linkage analyses, which are penetrance-independent, yielded Zmax LOD scores of 14.2 and 24.9 at D12S345, respectively, strongly supporting the mapping of the parkinsonism locus in this family to 12p11.23-q13.11. This chromosome region is different from any known locus for hereditary parkinsonism, in keeping with the unique genetic features of the parkinsonism in this family. The nomenclature of PARK8 was assigned to the new locus.