title: Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase.
abstract: Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders.
authors.affiliation: Eccles Institute of Human Genetics, University of Utah, Salt Lake City, 84112, USA. diana.stafforini@genetics.utah.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Stafforini
authors.forename: K
authors.initials: K
authors.lastname: Satoh
authors.forename: D L
authors.initials: DL
authors.lastname: Atkinson
authors.forename: L W
authors.initials: LW
authors.lastname: Tjoelker
authors.forename: C
authors.initials: C
authors.lastname: Eberhardt
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: T
authors.initials: T
authors.lastname: Imaizumi
authors.forename: S
authors.initials: S
authors.lastname: Takamatsu
authors.forename: G A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: T M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: P W
authors.initials: PW
authors.lastname: Gray
authors.forename: S M
authors.initials: SM
authors.lastname: Prescott
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000328:Adult; D000595:Amino Acid Sequence; D001249:Asthma / Q000209:etiology*; D001483:Base Sequence; D001665:Binding Sites; D002874:Chromosome Mapping; D006801:Humans; D007564:Japan; D008969:Molecular Sequence Data; D010740:Phospholipases / Q000235:genetics; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics*; D017354:Point Mutation
chemical_list: D010740:Phospholipases; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase