Iacomino Michele, Baldassari Simona, Tochigi Yuki, Kośla Katarzyna, Buffelli Francesca, Torella Annalaura, Severino Mariasavina, Paladini Dario, Mandarà Luana, Riva Antonella, Scala Marcello, Balagura Ganna, Accogli Andrea, Nigro Vincenzo, Minetti Carlo, Fulcheri Ezio, Zara Federico, Bednarek Andrzej K, Striano Pasquale, Suzuki Hiroetsu, Salpietro Vincenzo
Unit of Medical Genetics, IRCCS Istituto "Giannina Gaslini", Genoa, Italy.
Laboratory of Veterinary Physiology, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashinoi, Japan.
Front Neurosci. 2020 Jun 11;14:644. doi: 10.3389/fnins.2020.00644. eCollection 2020.
Mutations in the gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a -deficient human fetus from this family. A similar disorganization of cortical layers was identified in rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the gene in migrating neurons across different species.
该基因的突变会导致一系列极为罕见的神经发育和脑退行性疾病，在动物模型以及人类中都有很高的过早死亡可能性。编码的Wwox蛋白是一种含WW结构域的氧化还原酶，参与包括肿瘤抑制、细胞生长/分化和类固醇代谢调节等关键生物学过程，但其在神经发育中的作用尚不太清楚。我们分析了一个受多种产前和产后异常影响的家庭的外显子组，这些异常包括小脑蚓部发育不全、严重的神经发育障碍和难治性癫痫，并鉴定出一个导致过早终止密码子的纯合突变。在这个家庭中一名缺乏该基因的人类胎儿发育中的大脑中，发现由于颗粒细胞层和分子细胞层结构缺陷导致大脑皮层发育异常。在围产期阶段研究的缺乏该基因的大鼠（携带破坏活性Wwox C末端结构域的纯合截短突变）中也发现了类似的皮层层紊乱。对缺乏Wwox的人类神经祖细胞进行的转录组分析显示，一些编码微管蛋白、驱动蛋白及相关蛋白的与神经元迁移相关基因的表达受损。这些发现表明，Wwox的缺失可能会影响不同的细胞骨架成分并改变产前皮层发育，突出了该基因在不同物种中对迁移神经元的调节作用。
