The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

Int J Mol Sci. 2018 Jul 30;19(8):2218. doi: 10.3390/ijms19082218.

Abstract

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype⁻phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

Keywords: clinical informatics; disorder of glycosylation; modifier genes; variant analysis.

MeSH terms

  • Congenital Disorders of Glycosylation / diagnosis*
  • Congenital Disorders of Glycosylation / genetics*
  • Genetic Association Studies
  • Glycosylation
  • Humans
  • Models, Molecular
  • Mutation*
  • Mutation, Missense
  • Phenotype
  • Phosphotransferases (Phosphomutases) / chemistry
  • Phosphotransferases (Phosphomutases) / genetics*
  • Protein Conformation

Substances

  • Phosphotransferases (Phosphomutases)
  • phosphomannomutase 2, human