SLC35A2 (Solute Carrier Family 35 Member A2)

This review summarizes the molecular function of SLC35A2, clinical phenotypes of congenital and somatic variants, insights from functional assays and animal models, and therapeutic perspectives including galactose supplementation and precision medicine. We aim to provide an integrative synthesis of human genetics, neuropathology, glycomics, and translational approaches.

A prognostic model based on primary location-related genes was developed to predict prognosis and chemotherapy response in RCC. MX1 was identified as a pivotal target that promotes angiogenesis and chemoresistance, thereby providing a potential therapeutic strategy for patients with RCC.

Our results demonstrate that loss of SLC35A2 function in oligodendrocytes is sufficient to reproduce pathological and clinical features observed in human mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy. Spontaneous seizures in the absence of direct neuronal genetic abnormalities highlight a central role for oligodendrocyte dysfunction and hypomyelination in epileptogenesis. These findings challenge the neuron-centric view of epilepsy and suggest that targeting glial dysfunction may offer novel therapeutic opportunities. Further studies are warranted to delineate cellular interactions driving epileptogenesis and to explore glia-centered treatment strategies for drug-resistant epilepsies.

These phenotypes were recapitulated by in utero silencing of rat Slc35a2 gene. We successfully developed an in vivo mosaic model for the characterization of SLC35A2 variants identified in MOGHE patients and demonstrated that the expression of single SLC35A2 variants triggers the pathophysiological cascade associated with SLC35A2 dysfunction in neurons.

Furthermore, our CRC cell models revealed the tumor-promoting role of SLC35A2 and discovered that the upregulation of SLC35A2 is associated with chemoresistance against irinotecan...This may be due to its involvement in regulating cancer cell metabolic reprogramming, promoting tumor progression, modulating the immune landscape, and influencing treatment response. Consequently, SLC35A2 could serve as a significant prognostic factor and a potential therapeutic target in CRC.

This high-resolution cell type mapping of MOGHE lesions in clinical samples unveils neuronal and glial populations affected by the disease and provides novel insights into the pathophysiological mechanisms of MOGHE.

This case suggests the existence of a condition with similar histological findings to MOGHE but without epilepsy. The authors propose naming this condition "mild malformation of cortical development with oligodendroglial hyperplasia and no epilepsy." https://thejns.org/doi/10.3171/CASE24827.

The use of β-peptide-loaded sEVs further amplifies anti-metastatic effects, as demonstrated in vivo mouse models and molecular analyses. These findings underscore the therapeutic potential of glycosylation-modified sEVs in enhancing immune responses and controlling BC metastasis.

Notably, this hypomyelination pattern decreased with age. These results suggested a role for the SLC35A2 protein in the pathogenesis of MOGHE and indicated the presence of additional myelin-associated pathomechanisms in those individuals who do not carry a pathogenic SLC35A2 variant.

The genetic landscape of infantile epileptic spasms syndrome due to focal malformations comprises germline and somatic variants in a range of genes, with mTORopathies and SLC35A2-related mild malformation of cortical development with oligodendroglial hyperplasia being the major causes. Multimodal data integration incorporating genetic data aids in optimizing diagnostic pathways and can guide surgical decision-making and inform future research and therapeutic interventions.

The study emphasizes the clinical pearls indicative of the rare disease, which may facilitate early recognition and appropriate selection of treatments. The included studies were case reports or series, which were mainly limited by selection and reporting biases.

Additionally, chemoenzymatic glycan labeling in lesions demonstrated N-glycan damage of heterotopic neurons, suggesting a potential diagnostic approach for MOGHE. Our findings provide a comprehensive somatic landscape of MOGHE and a rich resource of somatic SLC35A2 variant-related glycoform and glycoprotein abnormalities, thereby unveiling valuable insights into compromised N-glycosylation and MOGHE formation.