title: Genetic characterization of myeloperoxidase deficiency in Italy.
abstract: Hereditary myeloperoxidase (MPO) deficiency (MPOD) is the most common neutrophil biochemical defect, and is characterized by a lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPOD in Italy, a population screening was carried out to detect mutations in the MPO gene. Of approximately 40,000 individuals analyzed, seven partial and eight total MPO-deficient subjects were identified. The genetic characterization of the subjects showed the presence of three already-known mutations (c.752T>C, c.1705C>T, and c.1566_1579del14) and six novel mutations: four missense mutations (c.995C>T, c.1112A>G, c.1715T>G, and c.1927T>C), then a deletion of an adenine within exon 3 (c.325delA) and a mutation within the 3' splice site of intron 11 (c.2031-2A>C). The novel missense mutations cause the substitution of the residues p.A332V, p.D371G, p.L572W, and p.W643R, respectively, and the potential structural changes are discussed. The c.325delA deletion causes a shift of the reading frame with the occurrence of a premature stop codon within the propeptide. Then, considering the difficulty in obtaining bone marrow samples from MPO-deficient subjects to study MPO mRNA splicing in vivo, we set up an eukaryotic expression system to investigate how the c.2031-2A>C mutation alters the MPO pre-mRNA splicing. The activation of a cryptic 3' splice site located 109nt upstream of the authentic 3' splice site was observed. The 109nt-insertion causes a shift in the reading frame that should lead to the generation of an abnormal MPO precursor lacking the enzymatic activity.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchetti
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Patriarca
authors.forename: G Pietro
authors.initials: GP
authors.lastname: Solero
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Baralle
authors.forename: Maurizio
authors.initials: M
authors.lastname: Romano
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D003677:Deficiency Diseases / Q000175:diagnosis; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009195:Peroxidase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D017354:Point Mutation; D012326:RNA Splicing
chemical_list: D009195:Peroxidase