Sadovnick A Dessa, Traboulsee Anthony L, Bernales Cecily Q, Ross Jay P, Forwell Amanda L, Yee Irene M, Guillot-Noel Lena, Fontaine Bertrand, Cournu-Rebeix Isabelle, Alcina Antonio, Fedetz Maria, Izquierdo Guillermo, Matesanz Fuencisla, Hilven Kelly, Dubois Bénédicte, Goris An, Astobiza Ianire, Alloza Iraide, Antigüedad Alfredo, Vandenbroeck Koen, Akkad Denis A, Aktas Orhan, Blaschke Paul, Buttmann Mathias, Chan Andrew, Epplen Joerg T, Gerdes Lisa-Ann, Kroner Antje, Kubisch Christian, Kümpfel Tania, Lohse Peter, Rieckmann Peter, Zettl Uwe K, Zipp Frauke, Bertram Lars, Lill Christina M, Fernandez Oscar, Urbaneja Patricia, Leyva Laura, Alvarez-Cermeño Jose Carlos, Arroyo Rafael, Garagorri Aroa M, García-Martínez Angel, Villar Luisa M, Urcelay Elena, Malhotra Sunny, Montalban Xavier, Comabella Manuel, Berger Thomas, Fazekas Franz, Reindl Markus, Schmied Mascha C, Zimprich Alexander, Vilariño-Güell Carles
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
G3 (Bethesda). 2016 Jul 7;6(7):2073-9. doi: 10.1534/g3.116.030841.
Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
多发性硬化症（MS）是一种病因复杂的常见神经系统疾病。在此，我们描述了一个多发性MS家族的特征，该家族确定纤溶酶原（PLG）中一种罕见的错义变体（p.G420D）为MS的一个假定遗传风险因素。对来自加拿大的2160例MS患者和886名对照进行PLG p.G420D（rs139071351）基因分型，又发现了10例先证者、2例散发性患者和1例携带该变体的对照。在携带rs139071351变体的家族中进行分离分析，在30名被诊断为MS的家族成员中有26名、14名未患病的父母以及30名未被诊断出患有该病的家族成员中有12名携带p.G420D。尽管外显率大幅降低，但连锁分析支持PLG p.G420D与疾病的共分离。对来自加拿大、法国、西班牙、德国、比利时和奥地利的14446例患者和8797名对照进行PLG p.G420D基因分型，尽管患者中的总体患病率较高（比值比=1.32；95%置信区间=0.93 - 1.87），但未发现与疾病有显著关联（P = 0.117）。为了评估其他罕见变体是否对MS风险有影响，我们对293例先证者的PLG进行了测序，并对病例和对照中的所有罕见变体进行了基因分型。该分析确定了9种罕见的错义变体，尽管其中3种仅在MS患者中观察到，但分离分析不支持其致病性。由于PLG参与免疫系统反应、血脑屏障通透性和髓鞘降解，它是MS一个合理的生物学候选因素。此外，与对照组相比，其激活级联反应的成分在MS患者中已显示出活性或表达增加；需要进一步研究以阐明PLG是否与MS易感性有关。
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