Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease
Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease
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DOI：
10.1093/brain/aws161
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发表时间：
2012-09-01
期刊：
影响因子：
14.5
通讯作者：
Singleton, Andrew B.
中科院分区：
文献类型：
--
作者：
Johnson, Janel O.;Gibbs, J. Raphael;Singleton, Andrew B.
Brown-Vialetto-Van Laere 综合征于 1894 年首次被描述为一种罕见的神经退行性疾病，其特征是进行性感觉神经性耳聋并伴有儿童期肌萎缩侧索硬化症。 SLC52A3（以前称为 C20orf54）基因是已知的三种核黄素转运蛋白基因之一，最近已被证明是许多严重的 Brown-Vialetto-Van Laere 综合征病例的基础。然而，存在这种疾病的病例和家庭似乎不是由 SLC52A3 突变引起的。我们结合使用连锁和外显子组测序来鉴定黎巴嫩 Brown-Vialetto-Van Laere 亲属中引起疾病的突变，该亲属的受影响成员的 SLC52A3 突变呈阴性。我们发现核黄素转运蛋白基因家族第二个成员（基因符号：SLC52A2）的新突变是该家族疾病的原因。在 44 名筛查对象中，另外一名受试者也发现了相同的突变。在这组 44 名患者中，我们还发现了另外两例具有 SLC52A3 突变的病例，但没有一例具有该基因家族其余成员 SLC52A1 的突变。我们相信这有力地支持了核黄素转运缺陷在 Brown-Vialetto-Van Laere 综合征中发挥重要作用的观点。初步研究表明，具有 SLC52A3 缺陷的患者对核黄素治疗有临床和生化反应。显然，这对于此处确定的 SLC52A2 突变阳性患者来说是一种极好的候选疗法。其中一名患者的初步核黄素治疗显示出有希望的结果。
Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.