PMM2, short for phosphomannomutase 2, is a crucial gene whose encoded enzyme is involved in the conversion of Man-6-P to Man-1-P. This process is part of the pathway that generates guanosine 5'-diphospho-D-mannose, a nucleotide-activated sugar essential for constructing protein oligosaccharide chains [1]. Mutations in PMM2 lead to phosphomannomutase 2 deficiency (PMM2-CDG), a congenital disorder of glycosylation [1].

Mutant PMM2 causes reduced production of Man-1-P, resulting in low levels of guanosine 5'-diphospho-D-mannose, which impairs protein glycosylation [1]. PMM2-CDG presents as a multisystem disorder with central nervous system involvement, hepatopathy, gastrointestinal and cardiac symptoms, endocrine dysfunction, abnormal coagulation, and renal abnormalities such as cystic kidney, mild proteinuria, and congenital nephrotic syndrome [2]. In vitro neural models from PMM2-CDG individuals show aberrant neural activity, impaired protein glycosylation, mitochondrial structure, and glucose metabolism, with PMM2 enzymatic activity correlating with symptom severity [3]. No direct genotype-phenotype correlations have been identified, but variants in the stabilization/folding domain result in a less severe phenotype, while those in the dimerization domain lead to a worse clinical course [4]. Transcriptomic analysis of patient-derived fibroblasts identified dysregulated pathways like Senescence, Bone regulation, Cell adhesion, ECM, and Response to cytokines, and treatment with a pharmacological chaperone reverted some gene expression changes [5].

In conclusion, PMM2 is essential for the production of a key sugar for protein glycosylation. Research on PMM2-related disorders, though not involving KO/CKO mouse models in the provided references, has revealed its significance in multiple biological systems and disease-associated pathways. Understanding PMM2's function provides insights into the pathophysiology of PMM2-CDG and potential therapeutic targets [1,2,3,4,5].