Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, et Collège de France, 67404, Illkirch, France,
Cerebellum. 2013 Dec;12(6):835-40. doi: 10.1007/s12311-013-0489-4.
We previously described a new form of recessive ataxia, Salih ataxia, in a large consanguineous Saudi Arabian family with three affected children carrying a new identified mutation in the KIAA0226 gene (c.2624delC; p.Ala875ValfsX146) coding for Rubicon. The pathogenicity of such mutation remains to be identified. Hence, we address the cellular impact of Rubicon p.Ala875ValfsX146 on endosomal/lysosomal machinery on cultured cells. We confirm that Rubicon colocalizes with the late endosome marker Rab7 and demonstrate that it also colocalizes with LampI at lysosomes. The Salih ataxia mutation leads to a diffuse cytosolic distribution and mislocalized protein from the late endosomes, indicating that deletion of the diacylglycerol binding-like motif in the mutant protein interferes with normal Rubicon subcellular localization and confirming the pathogenicity of the mutation.
我们之前在一个有三个受影响孩子的大型沙特阿拉伯血缘家族中描述了一种新的隐性共济失调，即 Salih 共济失调，该家族携带有新发现的 Rubicon 基因（c.2624delC；p.Ala875ValfsX146）中的突变。该突变的致病性仍有待确定。因此，我们研究了 Rubicon p.Ala875ValfsX146 对培养细胞内内体/溶酶体机制的细胞影响。我们证实 Rubicon 与晚期内体标记物 Rab7 共定位，并证明它也与溶酶体中的 LampI 共定位。Salih 共济失调突变导致突变蛋白弥散性分布在细胞质中，并且蛋白定位错误，从晚期内体中移出，表明突变体蛋白中二酰基甘油结合样基序的缺失干扰了正常的 Rubicon 亚细胞定位，证实了该突变的致病性。
