Novel mutation (Gly280Ala) in the ATP-binding domain of glycerol kinase causes severe hyperglycerolemia

Abstract

Glycerol kinase deficiency is a rarely diagnosed X-linked recessive disorder which occurs as a complex form together with the adrenal hypoplasia congenita (AHC) or with Duchenne muscular dystrophy (DMD) or as an isolated form either symptomatic or asymptomatic. We report the case of a male adult who had pseudo-hypertriglyceridemia (falsely elevated triglycerides of 552 mg/dl) refractory to lipid-lowering therapy for more than 15 years. Further investigations revealed an isolated, asymptomatic glycerol kinase deficiency. Using polymerase chain reaction and direct DNA sequencing, a novel missense mutation Gly280Ala in the Xp21.3 glycerol kinase gene was found. Comparison between human and E.coli glycerol kinase showed that the mutation affects a highly conserved amino acid in an ATP-binding domain in the active centre. This mutation is assumed to destabilize a hydrogen bond between ligand and enzyme resulting in a reduced activity of glycerol kinase and therefore in hyperglycerolemia.