Mosaic expression of SLC35A2 pathogenetic variants impairs neuronal migration and dendritogenesis in the developing cortex

作者：Antonio Falace, Léa Corbières, Lucas Silvagnoli, Cristiana Pelorosso, Clara Tuccari di San Carlo, Emmanuelle Buhler, Zeinab Hoteit, Š. Bauer, Beatrice Risso, Quénol Cesar, Emilie Pallesi‐Pocachard, Jean‐Bernard Manent, Carmen Barba, Renzo Guerrini, Carlos Cardoso, Valerio Conti · 发表于：Human Molecular Genetics · 年份：2025 · DOI：10.1093/hmg/ddaf156 · 被引用次数：3 · 研究领域：Epilepsy research and treatment、Genetics and Neurodevelopmental Disorders、Drug Transport and Resistance Mechanisms

Brain somatic variants in the SLC35A2 gene, encoding for a Golgi galactose transporter, represent the major cause of mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). Clinical features associated with MOGHE include early-onset epileptic encephalopathy, drug-resistant focal epilepsy with developmental delay, and intellectual disability. Half of somatic SLC35A2 variants identified in MOGHE patients are predicted to encode full-length SLC35A2 protein or stable protein products. We investigated the pathophysiological basis of MOGHE by analyzing the functional consequences of SLC35A2 pathogenetic variants in vitro and in vivo models. We assessed how different SLC35A2 variants impact protein stability and expression in transfected cellular models. We used in utero electroporation in the rat brain to model mosaic expression of SLC35A2 pathogenetic variants in the cerebral cortex and assessed their effect on neurons migration and morphology. We found that SLC35A2 variants identified in MOGHE patients variably impact on SLC35A2 protein expression. In utero expression of a SLC35A2 missense (p.G282A) or frameshift (p.F280Tfs*10) variants resulted in neuronal heterotopia in the white matter and impaired dendritogenesis at postnatal stages, suggesting a cell autonomous role for SLC35A2 in neuronal development. These phenotypes were recapitulated by in utero silencing of rat Slc35a2 gene. We successfully developed an in vivo mosaic model for t...