Abstract
Phosphomannomutase 2 (PMM2) deficiency is the most common congenital disorders of glycosylation (CDG) with an estimated incidence ranging from 1:20,000 to 1:80,000. Patients manifest a broad spectrum of clinical manifestations, with neurological deficits often emerging as the earliest sign, and may progress to severe multi-organ dysfunction. Mortality reaches 20% by the age of six, primarily due to severe infections, liver insufficiency, or cardiomyopathy. The pathophysiology of the tissue-specific complications remains unclear and there is currently no cure for the disease. In this study, we performed omics analyses of cerebella isolated from a mouse model of PMM2-CDG. RNA-Seq analysis revealed altered gene expression in pathways involved in immune responses and coagulation, while proteomic analysis of proteins enriched by lectin-affinity chromatography identified proteins required for neurodevelopment and neurotransmission. We validated our results by demonstrating significant downregulation of Neurexin-2 in the Pmm2 knockout (KO) mouse cerebella and showed that its reduced abundance can be reversed by AAV9- PMM2 gene treatment of the Pmm2 KO mice.