Communications Biology · 20 authors, 7 centres
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This study identified two novel FBP1 missense mutations in an adult patient with hypoglycemic lactic acidosis and characterized their effects on FBP1 protein expression and enzyme activity. The authors classified all known FBP1 missense mutations into three functional categories, highlighting protein misfolding as a key pathogenic mechanism for Type 2 mutations.
The study investigated fructose 1,6-bisphosphatase (FBPase) deficiency, an autosomal recessive disorder causing hypoglycemic lactic acidosis. Researchers identified compound heterozygous FBP1 mutations, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient. In vitro assays demonstrated that both mutations decreased FBP1 protein expression and abolished FBPase enzyme activity. Proteomic analysis showed mutant FBP1 proteins increased interactions with molecular chaperones (HSP70, HSP90, HSP60, TCP1) and aggregated in the endoplasmic reticulum. By reviewing 15 known missense mutations, the authors classified them into three types: Type 1 (activity loss without expression change), Type 2 (activity loss with decreased expression due to misfolding), and Type 3 (likely nonpathogenic). The findings suggest protein misfolding is a key pathogenic mechanism, particularly for Type 2 mutations, and propose that pharmacological chaperone therapy may be beneficial for these patients.
