Congenital disorders of glycosylation (CDG) are a group of neurometabolic disorders characterized by genetic defects in the highly conserved cellular glycosylation machinery. A majority of CDG patients have biallelic mutations in PMM2, a gene encoding the protein phosphomannomutase 2 required to activate mannose monosaccharides for N-linked protein glycosylation. PMM2-CDG patients suffer from multi-systemic involvement, and all patients uniformly suffer from neurological impairment that is prominent, progressive, and produces lifelong intellectual disability, ataxia and often seizures. Based on the genetic basis of CDG, we propose to establish and characterize a novel mouse model of PMM2-CDG to specifically investigate the function of PMM2 in neuronal and glial cells. We will also investigate the role of PMM2 in cerebellum development and function. With combined genetic, molecular, and behavioral approaches, we hope to not only reveal novel insight into the pathogenic mechanisms of CDG, but also to expedite the development of mechanism-based therapeutics to improve treatment. Moreover, our proposed study will provide the research community at large with innovative tools and resources to investigate the pathophysiology underlying a variety of glycosylation deficit-related disorders.
Glycosylation is an essential cellular process, its importance emphasized by the congenital disorders of glycosylation (CDG), a group of neurometabolic disorders with prominent neurological deficits due to genetic defects in the highly conserved cellular glycosylation machinery. Despite of many known genetic causes, the pathogenic mechanisms of CDG are poorly understood, thus limiting the development of diagnosis and treatment options. This proposal aims to investigate the pathophysiology of CDG with a focus on neurological impairment with Pmm2 deficiency in neuronal cells, glial cells, and the cerebellum.