Chiò Adriano, Mora Gabriele, Sabatelli Mario, Caponnetto Claudia, Lunetta Christian, Traynor Bryan J, Johnson Janel O, Nalls Mike A, Calvo Andrea, Moglia Cristina, Borghero Giuseppe, Trojsi Francesca, La Bella Vincenzo, Volanti Paolo, Simone Isabella, Salvi Fabrizio, Logullo Francesco O, Riva Nilo, Carrera Paola, Giannini Fabio, Mandrioli Jessica, Tanel Raffaella, Capasso Margherita, Tremolizzo Lucio, Battistini Stefania, Murru Maria Rita, Origone Paola, Zollino Marcella, Penco Silvana, Mazzini Letizia, D'Alfonso Sandra, Restagno Gabriella, Brunetti Maura, Barberis Marco, Conforti Francesca L
ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
Department of Neurological Rehabilitation, Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Milano, Milano, Italy.
Neurobiol Aging. 2016 Mar;39:218.e5-8. doi: 10.1016/j.neurobiolaging.2015.11.027. Epub 2015 Dec 8.
There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients.
有迹象表明，家族性肌萎缩侧索硬化症（ALS）和散发性ALS的表型及预后部分受遗传和环境因素调控，这支持了ALS是一种多因素疾病的理论。本文旨在评估ATXN2中间长度重复序列在一大组携带致病性C9ORF72 GGGGCC六核苷酸重复序列的意大利和撒丁岛ALS患者及对照中的作用。通过意大利ALS遗传联盟的数据库共识别出1972例ALS病例，该联盟是一项包括意大利各地18个ALS中心的合作项目。研究人群包括：（1）276例携带C9ORF72扩增的意大利ALS病例和57例撒丁岛ALS病例；（2）1340例未携带C9ORF72扩增的意大利ALS病例和299例撒丁岛ALS病例。还评估了总共1043名健康对照。大多数意大利和撒丁岛的病例及对照对于ATXN2基因的22/22或23/23重复序列是纯合子，或者对于22/23重复序列是杂合子。在3例（0.6%）携带C9ORF72扩增的意大利ALS病例中检测到ATXN2中间长度重复序列等位基因（≥28），在携带该扩增的撒丁岛ALS病例中未检测到，在60例（4.3%）未携带该扩增的意大利病例中检测到，在6例（2.0%）未携带C9ORF72扩增的撒丁岛ALS病例中检测到。在12例（1.5%）意大利对照和1例（0.84%）撒丁岛对照中发现了中间长度重复序列等位基因。因此，携带C9ORF72扩增的ALS患者中ATXN2多聚谷氨酰胺中间长度重复序列的频率低于对照（意大利病例，p = 0.137；撒丁岛病例，p = 0.0001）以及未携带C9ORF72扩增的ALS患者（意大利病例，p = 0.005；撒丁岛病例，p = 0.178）。在我们针对携带C9ORF72 GGGGCC六核苷酸重复序列扩增的意大利和撒丁岛ALS患者的大型研究中，与年龄、性别和种族匹配的对照相比，ATXN2多聚谷氨酰胺中间长度并不代表ALS风险的修饰因子，这与非C9ORF72突变患者不同。
