Lrrk2 pathogenic substitutions in Parkinson's disease
Lrrk2 pathogenic substitutions in Parkinson's disease
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DOI：
10.1007/s10048-005-0005-1
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发表时间：
2005-12-01
期刊：
影响因子：
2.2
通讯作者：
Farrer, MJ
中科院分区：
文献类型：
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作者：
Mata, IF;Kachergus, JM;Farrer, MJ
富含亮氨酸重复序列激酶2（LRRK2）突变与常染色体显性帕金森综合征有关，与典型的左旋多巴反应性帕金森病一致。该基因定位于染色体12q12，编码一种大型多功能蛋白质。为了鉴定新的LRRK2突变，我们对100名有帕金森症家族史的受影响先证者进行了测序。在所有先证者中也进行半定量分析以鉴定LRRK2基因组增殖或缺失。在欧洲、亚洲和北美许多地区的运动障碍诊所提到的这些运动障碍中，帕金森病分离为常染色体显性性状。分析了LRRK2基因的所有51个外显子，并在对照组内评估了所有新序列变体的频率。突变与疾病的分离已经在较大的多重家族中进行了研究。我们的研究确定了26个编码变体，包括15个非同义氨基酸取代，其中三个影响相同的密码子（R1441C，R1441G和R1441H）。这些编码变化中有7个似乎是致病性的，因为它们与疾病分离，并且在对照组中未被识别。未发现倍增或缺失。
Leucine-rich repeat kinase 2 (LRRK2) mutations have been implicated in autosomal dominant parkinsonism, consistent with typical levodopa-responsive Parkinson's disease. The gene maps to chromosome 12q12 and encodes a large, multifunctional protein. To identify novel LRRK2 mutations, we have sequenced 100 affected probands with family history of parkinsonism. Semiquantitative analysis was also performed in all probands to identify LRRK2 genomic multiplication or deletion. In these kindreds, referred from movement disorder clinics in many parts of Europe, Asia, and North America, parkinsonism segregates as an autosomal dominant trait. All 51 exons of the LRRK2 gene were analyzed and the frequency of all novel sequence variants was assessed within controls. The segregation of mutations with disease has been examined in larger, multiplex families. Our study identified 26 coding variants, including 15 nonsynonymous amino acid substitutions of which three affect the same codon (R1441C, R1441G, and R1441H). Seven of these coding changes seem to be pathogenic, as they segregate with disease and were not identified within controls. No multiplications or deletions were identified.