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bioRxiv · 10.1101/2025.08.11.669733

AAV-based gene replacement reverses Neurexin-2 downregulation in the cerebellum of a mouse model of phosphomannomutase 2 deficiency (PMM2-CDG)

Zhong, M.-l.·Lai, K.
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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.

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Zhong, M.-l., Lai, K.. 2025-08-14. AAV-based gene replacement reverses Neurexin-2 downregulation in the cerebellum of a mouse model of phosphomannomutase 2 deficiency (PMM2-CDG). https://doi.org/10.1101/2025.08.11.669733

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