常染色体显性帕金森病中的 RAB32 Ser71Arg:联系、关联和功能分析。

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Lancet Neurology Pub Date : 2024-06-01 Epub Date: 2024-04-10 DOI:10.1016/S1474-4422(24)00121-2
Emil K Gustavsson, Jordan Follett, Joanne Trinh, Sandeep K Barodia, Raquel Real, Zhiyong Liu, Melissa Grant-Peters, Jesse D Fox, Silke Appel-Cresswell, A Jon Stoessl, Alex Rajput, Ali H Rajput, Roland Auer, Russel Tilney, Marc Sturm, Tobias B Haack, Suzanne Lesage, Christelle Tesson, Alexis Brice, Carles Vilariño-Güell, Mina Ryten, Matthew S Goldberg, Andrew B West, Michele T Hu, Huw R Morris, Manu Sharma, Ziv Gan-Or, Bedia Samanci, Pawel Lis, Maria Teresa Periñan, Rim Amouri, Samia Ben Sassi, Faycel Hentati, Francesca Tonelli, Dario R Alessi, Matthew J Farrer
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引用次数: 0

摘要

背景:帕金森病是一种进行性神经退行性疾病,其病因是多因素的,其中遗传风险因素起了一定作用。RAB GTPases 是 LRRK2 的调节因子和底物,而 LRRK2 基因的变异是帕金森病的重要风险因素。我们旨在探索家族性帕金森病病例中 RAB GTPases 的遗传变异:我们对来自加拿大和突尼斯无遗传病因的帕金森病家庭的原发性帕金森病患者进行了全外显子组测序,这些患者是从应用神经遗传学中心(加拿大不列颠哥伦比亚省温哥华市)招募的,该中心是一个国际联盟,包括来自 24 个国家 36 个地点的帕金森病患者。对 61 个 RAB GTP 酶进行了基因筛选,并对病例亲属中的候选变体进行了基因分型,以通过关联分析评估疾病的分离情况。此外,还对特发性帕金森病患者以及年龄和性别匹配的对照组进行了基因分型,以评估变体频率。所有参与者的年龄都在 18 岁或以上。利用从公开的临床基因组数据库(AMP-PD、GP2 和 100 000 基因组计划)和德国私人临床诊断数据库(图宾根大学)中获得的生物信息学数据,通过病例对照关联分析对测序和基因分型结果进行了验证。对临床和病理结果进行了总结,并确定了单倍型。还进行了体外研究,以调查蛋白质相互作用和酶活性:2010年6月1日至2017年5月31日期间,来自加拿大和突尼斯的130名受试者(47[36%]名女性和83[64%]名男性;平均年龄72-7岁[SD 11-7;范围38-96];109名白种欧洲血统、18名北非血统、2名东亚血统和1名西班牙血统)接受了全外显子组测序。发现了 15 个 RAB GTPase 基因变异,其中 RAB32 变异 c.213C>G(Ser71Arg)与 3 个家族中的常染色体显性帕金森病共患病(9 个患者;非参数连锁 Z score=1-95;p=0-03)。此外,还对 2604 名无血缘关系的帕金森病患者和 344 名匹配的对照者进行了基因分型,又发现了来自五个国家(加拿大、意大利、波兰、土耳其和突尼斯)的五名 RAB32 变异者。通过数据库搜索,共纳入了6043名帕金森病患者和62 549名对照者,又从4个国家(加拿大、德国、英国和美国)发现了8名RAB32变体患者。总体而言,RAB32 c.213C>G(Ser71Arg)与帕金森病的相关性显著(比值比 [OR] 13-17,95% CI 2-15-87-23;P=0-0055;I2=99-96%)。帕金森病患者的年龄为 54-6 岁(SD 12-75,范围 31-81,n=16),三分之二的患者有帕金森病家族史。RAB32 Ser71Arg 杂合子共享一个共同的单倍型,但渗透性不完全。一名患者的尸检结果显示,中脑和丘脑有稀疏的神经纤维缠结病变,但无路易体病变。在功能研究中,RAB32 Arg71 对 LRRK2 激酶的激活水平高于 RAB32 Ser71:RAB32 Ser71Arg是帕金森病的一种新型遗传风险因素,具有较低的渗透性。该变异在多个种族的帕金森病患者中发现,且具有相同的单倍型。体外检测显示,RAB32 Arg71 可激活 LRRK2 激酶,这表明家族性帕金森病的不同遗传原因具有相同的机制。RAB32 Ser71Arg 的发现还表明,帕金森病的几种遗传病因起源于控制细胞内免疫。在未来的转化研究中应考虑这种共同的病因,同时需要对RAB32 Ser71Arg的全球流行病学进行评估,以便为遗传咨询提供信息:美国国立卫生研究院、加拿大卓越研究教席计划、帕金森病科学联盟、迈克尔-J-福克斯帕金森病研究基金会和英国医学研究委员会。
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RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

Background: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease.

Methods: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities.

Findings: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71.

Interpretation: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling.

Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

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来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
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