Myhre Ronny, Steinkjer Stina, Stormyr Alice, Nilsen Gina L, Abu Zayyad Hiba, Horany Khalid, Nusier Mohamad K, Klungland Helge
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
BMC Neurol. 2008 Dec 16;8:47. doi: 10.1186/1471-2377-8-47.
Parkinson's disease is a progressive neurodegenerative disorder, where most cases are sporadic with a late onset. In rare incidences familial forms of early-onset parkinsonism occur, and when recessively inherited, cases are often explained by mutations in either the parkin (PARK2) or PINK1 (PARK6) gene or on exceptional occasions the DJ-1 (PARK7) or ATP13A2 (PARK9) gene. Recessively inherited deletions/duplications and point mutations in the parkin gene are the most common cause of early-onset parkinsonism known so far, but in an increasing number of studies, genetic variations in the serine/threonine kinase domain of the PINK1 gene are found to explain early-onset parkinsonism.
In this study all families were from a population with a high incidence of consanguinity. We investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset parkinsonism for mutations both in the parkin and PINK1 gene. Exons and flanking regions were sequenced, and segregation patterns of genetic variation were assessed in members of the respective families. An exon dosage analysis was performed for all exons in both genes.
In the parkin gene, a three generation family was identified with an exon 4 deletion segregating with disease. Both affected were homozygous for the deletion that segregated on a haplotype that spanned the gene in a haplotype segregation analysis that was performed using additional markers. Exon dosage analysis confirmed the recessive pattern of inheritance with heterozygous deletions segregating in healthy family members. In the PINK1 gene we identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain. Both substitutions segregated with disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in two affected each. We also discuss common polymorphisms in the two genes found to be co-segregating within families.
Our results further extend on the involvement of PINK1 mutations in recessive early-onset parkinsonism with clinical features similar to carriers of parkin mutations.
帕金森病是一种进行性神经退行性疾病，大多数病例为散发性且发病较晚。在罕见情况下会出现早发性帕金森综合征的家族形式，当为隐性遗传时，病例通常由帕金森蛋白（PARK2）或PINK1（PARK6）基因的突变所解释，在特殊情况下也可由DJ - 1（PARK7）或ATP13A2（PARK9）基因的突变所解释。帕金森蛋白基因的隐性遗传缺失/重复和点突变是迄今为止已知的早发性帕金森综合征最常见的病因，但在越来越多的研究中，发现PINK1基因丝氨酸/苏氨酸激酶结构域的遗传变异也可解释早发性帕金森综合征。
在本研究中，所有家族均来自近亲结婚率高的人群。我们调查了11个近亲家族，这些家族中有17例患有隐性遗传的早发性帕金森综合征，检测其帕金森蛋白和PINK1基因的突变情况。对基因外显子及其侧翼区域进行测序，并评估各个家族成员中遗传变异的分离模式。对两个基因的所有外显子进行外显子剂量分析。
在帕金森蛋白基因中，鉴定出一个三代家族，其4号外显子缺失与疾病共分离。两名患者均为该缺失的纯合子，在使用额外标记进行的单倍型分离分析中，该缺失在跨越该基因的单倍型上分离。外显子剂量分析证实了隐性遗传模式，杂合缺失在健康家族成员中分离。在PINK1基因中，我们鉴定出两个新的假定致病性替代突变，P416R和S419P，位于丝氨酸/苏氨酸激酶结构域的一个保守基序中。这两个替代突变在各自家族中均与疾病共分离，符合隐性遗传模式，且在两名患者中均为纯合子。我们还讨论了在家族中共分离的这两个基因中的常见多态性。
我们的结果进一步扩展了PINK1突变在具有与帕金森蛋白突变携带者相似临床特征的隐性早发性帕金森综合征中的作用。
