Klein Christine, Djarmati Ana, Hedrich Katja, Schäfer Nora, Scaglione Cesa, Marchese Roberta, Kock Norman, Schüle Birgitt, Hiller Anja, Lohnau Thora, Winkler Susen, Wiegers Karin, Hering Robert, Bauer Peter, Riess Olaf, Abbruzzese Giovanni, Martinelli Paolo, Pramstaller Peter P
Department of Neurology, University of Lübeck, Lübeck, Germany.
Eur J Hum Genet. 2005 Sep;13(9):1086-93. doi: 10.1038/sj.ejhg.5201455.
Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2+/-5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2+/-9.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (-21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.
隐性遗传的早发性帕金森病（EOP）与Parkin、DJ-1和PINK1基因的突变有关。我们研究了65例意大利患者（平均发病年龄：43.2±5.4岁，62例散发性，3例家族性）中这三个基因的突变发生率，这些患者的入选标准为发病年龄等于或小于51岁。所有病例的临床特征均与特发性帕金森病相符。为了检测Parkin、DJ-1和PINK1基因中的小序列改变，我们对这些基因的所有编码外显子进行了常规突变分析（SSCP/dHPLC/测序）。为了检测PINK1基因中外显子重排的存在，我们建立了一种新的定量双链PCR检测方法。使用先前报道的方案排除了Parkin和DJ-1基因的基因剂量改变。5例患者（8%；1名女性/4名男性；平均发病年龄：38.2±9.（范围为25 - 49）岁）在所研究的基因之一中携带突变：3例有新的PINK1突变，其中1例出现两次（纯合子c.1602_1603insCAA；杂合子c.1602_1603insCAA；杂合子c.836G>A），2例患者有已知的Parkin突变（杂合子c.734A>T和c.924C>T；杂合子c.924C>T）。所有突变携带者的家族史均为阴性，但有1例有震颤病史。此外，我们检测到1个新的多态性（c.344A>T）和4个PINK1基因的意义不明的新改变（-21G/A；IVS1+97A/G；IVS3+38_40delTTT；c.852C>T），但未检测到外显子重排。在DJ-1基因中未发现突变。我们队列中Parkin和PINK1基因中的突变携带者数量较少但相当，这表明在EOP中必须考虑PINK1基因。
