Ahmad Hena, Requena Teresa, Frejo Lidia, Cobo Marien, Gallego-Martinez Alvaro, Martin Francisco, Lopez-Escamez Jose A, Bronstein Adolfo M
Division of Brain Sciences, Imperial College, Charing Cross Hospital, London, United Kingdom.
National Hospital for Neurology & Neurosurgery, London, United Kingdom.
Front Genet. 2018 Mar 23;9:85. doi: 10.3389/fgene.2018.00085. eCollection 2018.
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt--transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias.
伴有神经病变和双侧前庭反射消失综合征的小脑共济失调（CANVAS）是一种病因不明的罕见疾病。我们报告了一个英国家庭，其患有推测为常染色体显性遗传的CANVAS，具有不完全外显率和可变表达性。外显子组测序在4号染色体上的基因中鉴定出一个罕见的错义变异：g.140058846 C>T，c.10G>A，p.A4T，该变异在所有受影响患者中均有分离。通过使用转导的BE(2)-M17细胞，我们发现突变的ELF2（mt-ELF2）基因增加了ATXN2的表达并降低了ELOVL5基因的表达，这两个基因分别是2型和38型脊髓小脑共济失调的致病基因。蛋白质印迹法和共聚焦显微镜检查均证实，在用表达mt-ELF2的慢病毒转导的BE(2)-M17细胞（CEE-mt-）中，ataxin-2增加，而在用表达野生型ELF2的慢病毒转导的细胞（CEE-wt-ELF2）中未观察到这种情况。此外，我们观察到在CEE-mt-转导的BE(2)-M17细胞中脂滴的数量和大小显著减少，而在CEE-wt-ELF2转导的BE(2)-M17细胞中则没有。此外，ELOVL5表达的变化可能与BE(2)-M17细胞中脂滴的减少有关。这项工作支持ELF2基因调节ATXN2和ELOVL5基因的表达，并在小脑共济失调的病理生理学中定义了新的分子联系。
