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.
Department of Clinical Pathology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki-City, Osaka 569-8686, Japan. cli002@poh.osaka-med.ac.jp
T
T
Nakagawa
T
T
Ikemoto
T
T
Takeuchi
K
K
Tanaka
N
N
Tanigawa
D
D
Yamamoto
A
A
Shimizu
D019943:Amino Acid Substitution; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D047209:Eosinophil Peroxidase; D004804:Eosinophils / Q000201:enzymology*; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D010544:Peroxidases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D017354:Point Mutation; D013329:Structure-Activity Relationship
D004247:DNA; D047209:Eosinophil Peroxidase; D010544:Peroxidases