Eosinophilic peroxidase deficiency: Identification of a point mutation (D648N) and prediction of structural changes

ABSTRACT Hereditary eosinophil peroxidase (EPO; EC 1.11.1.7) deficiency is a rare abnormality without clinical symptoms characterized by decreased or absent peroxidase activity and decreased volume of the granule matrix in eosinophils. Nearly 100 cases have been reported, but a specific mutation has been reported in only one case. We report the genetic analysis of an EPO-deficient subject and his family. The case was found by automated blood analyzer. Sequencing of the entire coding region of the EPO gene disclosed a novel mutation, a 2060 G-A transition (g. 2060G>A) causing an amino acid change from aspartic acid to asparagine (D648N). Both the son and daughter of the propositus inherited the G-A transition, and in vitro expression experiments suggest this transition is responsible for the deficiency. We then analyzed the location of the affected amino acid within this molecule using a structural model of EPO based on myeloperoxidase (MPO). Asn648 is on the inside of the molecule; changing D to N would cause loss of the electrostatic interaction with Arg146 which is crucial for disulfide bonds of the light chain in the N terminus.