Distinct phenotypic expression of two de novo missense mutations affecting the dimer interface of glucose-6-phosphate...

Mutations encoding class I glucose-6-phosphate dehydrogenase (G6PD) variants are associated with chronic nonspherocytic hemolytic anemia (CNSHA), the most severe phenotypic expression of G6PD deficiency. These mutations frequently affect the G6PD dimer interface that is essential for enzymatic activity. We detected two de novo missense mutations concerning residues located close together in the dimer interface in two patients with severe G6PD deficiency. A novel c.1225C>T missense mutation was identified in a male neonate who presented with hemolysis and severe hyperbilirubinemia and the predicted Pro409Ser substitution constituted a novel class I variant, designated G6PD Utrecht. G6PD deficiency in the second patient was due to the once previously reported class I variant G6PD Sumaré (Val431Gly). Structural analysis revealed that the mutated residues Pro409 and Val431, located on different subunits, interact directly across the subunit interface and perturb formation of the G6PD dimer upon mutation. Favism and mild chronic hemolysis characterized the phenotype of the patient with G6PD Sumaré which contrasts with the more severe clinical picture of the patient with G6PD Utrecht and, in addition, that of the patient originally described with G6PD Sumaré. We postulate that this G6PD variant is at the crossing between class I and class II G6PD deficiency and its ultimate phenotypic expression is either aggravated or ameliorated by other (extra)genetic factors.