Abstract：
OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.
METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.
RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.
CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.
METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.
RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.
CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.
摘要：
目的：在5％至10％的肌萎缩侧索硬化症（ALS）病例中有该疾病的家族史，在对已知的ALS相关基因进行全面研究后，其中30％没有可识别的潜在遗传原因。基于西班牙一个小地理区域的ALS发病率显着增加，这项工作的目的是在基因检测阴性的ALS病例中鉴定新的ALS相关基因.
方法：我们发现散发性和，尤其是,与可用的人口统计学和流行病学数据相比，西班牙小地区的家族性ALS病例。我们对来自该独特区域的12名ALS患者（其中5名是家族性）进行了全基因组测序。我们扩大了研究范围，包括受影响的家庭成员和来自更广泛周边地区的其他病例。
结果：我们在编码RNA结合蛋白的环AMP调节磷蛋白21（ARPP21）基因中发现了一个共有的错义突变（c.1586C>T;p.Pro529Leu），来自7个无关家庭的10例ALS患者。在其他引起ALS的基因中没有发现突变。
结论：虽然先前的研究已经排除了ARPP21在ALS中的因果作用，我们的结果强烈支持ARPP21是一种新的ALS致病基因.
方法：我们发现散发性和，尤其是,与可用的人口统计学和流行病学数据相比，西班牙小地区的家族性ALS病例。我们对来自该独特区域的12名ALS患者（其中5名是家族性）进行了全基因组测序。我们扩大了研究范围，包括受影响的家庭成员和来自更广泛周边地区的其他病例。
结果：我们在编码RNA结合蛋白的环AMP调节磷蛋白21（ARPP21）基因中发现了一个共有的错义突变（c.1586C>T;p.Pro529Leu），来自7个无关家庭的10例ALS患者。在其他引起ALS的基因中没有发现突变。
结论：虽然先前的研究已经排除了ARPP21在ALS中的因果作用，我们的结果强烈支持ARPP21是一种新的ALS致病基因.
