A new insight into PMM2 mutations in the French population

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Congenital disorder of Glycosylation type Ia (CDG-Ia) is an autosomal recessive condition.
• It results from defective N-glycosylation due to phosphomannomutase (PMM) deficiency, linked to PMM2 gene mutations.
• Over 75 mutations have been identified, causing central nervous system dysfunction and multiorgan failure.

Purpose of the Study:

• To identify and characterize novel PMM2 gene mutations in French CDG-Ia patients.
• To assess the functional impact of identified mutations on PMM enzyme activity and stability.
• To investigate the origins and prevalence of specific mutations within the French population.

Main Methods:

• Genetic analysis of 52 French families with CDG-Ia to identify PMM2 mutations.
• Expression of eight novel recombinant mutant PMM proteins in E. coli.
• Biochemical assays to determine enzyme activity and thermostability of mutant proteins.
• Haplotype analysis to trace mutation origins and identify founder effects.

Main Results:

• Thirty-eight distinct mutations were identified in 52 French families, including eleven previously unpublished mutations (eight missense, three splice).
• Most novel mutant proteins exhibited reduced activity and/or were thermolabile, confirming their pathogenicity.
• A founder effect was observed for the E139K mutation, prevalent in seven French families.
• The R141H mutation showed diverse haplotypes in France, suggesting a combination of European and distinct French origins.

Conclusions:

• This study expands the spectrum of known PMM2 mutations associated with CDG-Ia.
• Functional analysis confirms the pathogenicity of novel mutations, providing insights into disease mechanisms.
• Haplotype studies reveal distinct evolutionary histories for key mutations, with evidence of founder effects and potential older origins for R141H in France.