Lewy bodies and parkinsonism in families with parkin mutations
Lewy bodies and parkinsonism in families with parkin mutations
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DOI：
10.1002/ana.1132
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发表时间：
2001-09-01
影响因子：
11.2
通讯作者：
Langston, JW
中科院分区：
文献类型：
--
作者：
Farrer, M;Chan, P;Langston, JW
先前的工作已经确定，parkin 基因的复合突变和纯合性功能丧失会导致早发性常染色体隐性遗传帕金森症。传统上，这种疾病与黑质致密部和蓝斑中多巴胺能神经元的丧失有关，但没有路易体病理学。我们对 38 名早发性帕金森病患者（< 41 岁）的 Parkin 基因进行了测序。对两名携带突变的先证者进行了随访。对他们的家人进行了临床评估，对遗传和病理结果不知情。独立于性状进行染色体 6q25.2-27 单倍型分析，在 RNA 和蛋白质水平上检查 Parkin 基因表达。这些家族的单倍型分析揭示了共同的 6 号染色体，以及与疾病共分离的新的 40 bp 外显子 3 缺失。在较小亲属的先证者中，除了外显子 3 缺失之外，还发现了外显子 7 R275W 替换； RNA 分析表明突变发生在替代转录本上。然而，在尸检中，在来自较小亲属的先证者中发现了典型的特发性帕金森病的路易体病理。这些数据表明，复合杂合性 Parkin 突变和 Parkin 蛋白缺失可能导致早发性路易体病理学帕金森病，而半合子突变可能会增加对典型帕金森病的易感性。
Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early-onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early-onset Parkinson's disease (< 41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2-27 haplotype analysis was carried out independently of the trait, parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of Parkin protein may lead to early onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinson's disease.