PMM2 – PMM2-congenital disorder of glycosylation

PMM2-congenital disorder of glycosylation (PMM2-CDG) is the most common type I congenital disorder of glycosylation resulting from pathogenic variants in the PMM2 gene, which encodes the enzyme phosphomannomutase 2 central to N-glycan synthesis (PMID:11891694). Affected individuals present with early-onset multisystem disease including failure to thrive, hypotonia, inverted nipples, cerebellar hypoplasia, developmental delay and strabismus.

Genetic studies document autosomal recessive inheritance with compound heterozygous or homozygous variants in over 700 patients to date, with segregation in multiple families (PMID:23988505). Segregation analysis in large pedigrees including an Italian kindred with four affected and numerous consanguineous families confirms co-segregation of PMM2 variants with disease.

The variant spectrum exceeds 100 unique alleles, predominantly missense and loss-of-function changes. A recurrent example is c.710C>T (p.Thr237Met), first described in an African American patient and confirmed in multiple cohorts (PMID:11891694). Founder alleles such as p.Arg141His and p.Phe119Leu show population clustering and contribute to genotype-phenotype heterogeneity.

Functional assays across model systems demonstrate that PMM2 deficiency leads to hypoglycosylation. Patient-derived induced pluripotent stem cells exhibit 27% residual phosphomannomutase activity and reduced high-mannose N-glycans (PMID:26785728). Yeast models recapitulate genotype-phenotype relationships and enable drug screening (PMID:30530630), while a Pmm2R137H/F115L mouse mirrors growth defects and glycoprotein abnormalities seen in patients (PMID:27053713). Rescue of hypoglycosylation by wild-type PMM2 underscores the potential for targeted therapies.

No major conflicting data have been reported; however, a spectrum of severity from neonatal-lethal presentations to mild, late-onset cerebellar atrophy without intellectual disability highlights variable expressivity. Modifier genes and allelic combinations can influence residual enzyme activity and clinical outcome.

Integration of extensive case series, robust segregation data and concordant functional models supports a Definitive gene-disease association. Autosomal recessive PMM2-CDG should be considered in infants with hypotonia, dysmorphism and abnormal transferrin glycosylation. Key take-home: Molecular testing for PMM2 variants enables precise diagnosis, genetic counseling and paves the way for future therapeutic interventions.

References

• American journal of medical genetics • 2002 • A deletion-insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation-Ia. PMID:11891694
• Gene • 2013 • PMM2-CDG: phenotype and genotype in four affected family members. PMID:23988505
• Molecular & cellular proteomics : MCP • 2016 • Glycomic Characterization of Induced Pluripotent Stem Cells Derived from a Patient Suffering from Phosphomannomutase 2 Congenital Disorder of Glycosylation (PMM2-CDG). PMID:26785728
• G3 (Bethesda, Md.) • 2019 • Yeast Models of Phosphomannomutase 2 Deficiency, a Congenital Disorder of Glycosylation. PMID:30530630
• Human molecular genetics • 2016 • A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2. PMID:27053713

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