Linkage analysis of a Japanese family with autosomal dominant Parkinsonism

一个常染色体显性帕金森病日本家族的连锁分析

• 批准号: 12670616
• 负责人: HASEGAWA Kazuko
• 金额: $ 2.11万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670616/
• 关键词: Familial Parkinsonism; Park8; 家族制パーキンソニズム; ポジショナルクローニング; 常染色体優れ

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.

我们对一个常染色体显性帕金森病的日本家庭进行了全基因组连锁分析，该家庭表现出与普通帕金森病相一致的临床特征。参数两点连锁分析在D12S345 （12p11.21）处LOD得分最高，为4.32。对该标记周围13.6 cM区间进行参数多点连锁分析，LOD评分几乎一致高于4.0，在D12S85 （12q12）处Zmax为4.71。单倍型分析检测到D12S 1631和D12S339两个专性重组事件，并在12p11.2-q13.1的13.6 cM区间确定了疾病相关的单倍型。该单倍型为所有患者和一些未受影响的携带者共有，表明该疾病在该家族中的渗透是不完整的。这种低外显率表明环境或其他遗传因素改变了疾病的表达。与外显子无关的非参数2点和多点连锁分析结果显示，D12S345位点的Zmax LOD得分分别为14.2和24.9，这有力地支持了该家族帕金森病位点在12p11.23-q13.11的定位。这个染色体区域不同于任何已知的遗传性帕金森病的位点，与这个家族中帕金森病的独特遗传特征保持一致。新基因座命名为PARK8。

项目成果

M.Funayama, K.Hasegawa, H.Kowa et al.: "A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1."Ann Neurol. (in press). (2002)

M.Funayama、K.Hasekawa、H.Kowa 等人：“帕金森病的新基因座 (PARK8) 映射到染色体 12p11.2-q13.1。”Ann Neurol。

K Hasegawa, M Funayama, N.Matuura et al.: "Analysis of a-synuclein, parkin, tau, and UCH-L1 In a Japanese family of ADPD"Eur Neurol. 46. 20-24 (2001)

K Hasekawa、M Funayama、N.Matuura 等人：“日本 ADPD 家族中 a-突触核蛋白、parkin、tau 和 UCH-L1 的分析”Eur Neurol。

M.Funayura, K.Hasegawa, H.Kowa, et al.: "A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1"Ann Neurol. 51. 296-301 (2002)

M.Funayura、K.Hasekawa、H.Kowa 等人：“帕金森病 (PARK8) 的新基因座映射到染色体 12p11.2-q13.1”Ann Neurol。

T.Yokoyama, JI.Kusunoki, K.Hasegawa, et al.: "Distribution and dynamic process of neuronal cytoplasmic inclusion (NCI) in MSA"Neuropathology. 21. 145-154 (2001)

T.Yokoyama、JI.Kusunoki、K.Hasekawa 等：“MSA 中神经元细胞质包涵体 (NCI) 的分布和动态过程”神经病理学。

M Funayama, K Hasegawa, H Kowa, M Saito, S Tsuji, F Obata: "A new locus for Parkinson's disease (Park8) maps to chromosome 12p11.2-q13.1"Ann Neurol. 51. 296-301 (2002)

M Funayama、K Hasekawa、H Kowa、M Saito、S Tsuji、F Obata：“帕金森病的新基因座 (Park8) 映射到染色体 12p11.2-q13.1”Ann Neurol。