title: Mutations analysis of C1 inhibitor coding sequence gene among Portuguese patients with hereditary angioedema.
abstract: Mutations that modify the amino acid sequence of C1-INH (except Val458Met) are associated with HAE. More than 200 different mutations scattering the entire C1-INH gene have been reported. The main objective of this study was to report the mutational findings in a HAE cohort of 138 Portuguese patients followed in specialized consultation all over the country. DNA was extracted from peripheral blood with QiaSymphony BioRobot (QIAGEN Portugal). The sequence reactions were performed by using a DNA sequencing kit (Big Dye terminator cycle sequencing v1.1/v3.1 from Applied Biosystems) and sequencing products were immediately submitted to direct sequencing on an Applied Biosystem 3130 DNA Analyser. DNA sequences were analyzed at four different stages. Raw data and sequence alignments of all 8 exons and intron-exon boundaries were performed for each patient individually with SeqScape software and using SERPING1 gene NG_009625 of 24,300 bp (12-March-2011) as reference sequence. Sequence comparisons among patients and controls were performed with software CodonCode Aligner v.3.7 from CodonCode Corp and with Geneious 4.5 from Biomatters Lda. A total of 94 point mutations were observed among patients, and 67% of them were located on exon 8. In addition, we noticed one not described stop codon at position c.1459 C>T in three different patients. Translation termination was also found on exon 3 and 7, as a result of mutations at positions c.481A>7, c.1174C>T. In this population, the prevalence of the missense mutation p.Arg444Cys was 39 out of 42. Mutational analysis revealed 22 different pathogenic mutations, of which 64% were not described on HAE database. Although identification of disease causing mutations is not necessary to establish HAE diagnosis, studies on gene expression and characterization of rearrangements in SERPING1 gene are suggested in order to get new insights on function and genetic tests of C1 inhibitor.
authors.affiliation: Centro de Histocompatibilidade do Centro, Praceta Prof. Mota Pinto, Edifício São Jerónimo, Piso 4, 3001-301 Coimbra, Portugal. martinhoanton@gmail.com
authors.forename: A
authors.initials: A
authors.lastname: Martinho
authors.forename: J
authors.initials: J
authors.lastname: Mendes
authors.forename: O
authors.initials: O
authors.lastname: Simões
authors.forename: R
authors.initials: R
authors.lastname: Nunes
authors.forename: J
authors.initials: J
authors.lastname: Gomes
authors.forename: E
authors.initials: E
authors.lastname: Dias Castro
authors.forename: P
authors.initials: P
authors.lastname: Leiria-Pinto
authors.forename: M B
authors.initials: MB
authors.lastname: Ferreira
authors.forename: C
authors.initials: C
authors.lastname: Pereira
authors.forename: M G
authors.initials: MG
authors.lastname: Castel-Branco
authors.forename: L
authors.initials: L
authors.lastname: Pais
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D054179:Angioedemas, Hereditary / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D003174:Complement C1 Inactivator Proteins / Q000235:genetics*; D050718:Complement C1 Inhibitor Protein; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016366:Open Reading Frames; D011174:Portugal; D044465:White People
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; C469952:SERPING1 protein, human