title: Hereditary angioedema: the mutation spectrum of SERPING1/C1NH in a large Spanish cohort.
abstract: Hereditary angioedema (HAE) is a disease caused by defects in the C1 inhibitor gene (SERPING1/C1NH). We screened the entire C1NH gene for mutations in a large series of 87 Spanish families (77 with type I, and 10 with type II HAE) by SSCP, sequencing, Southern blotting, and quantitative multiplex PCR of short fluorescent fragments (QMPSF), and we characterized several defects at the mRNA level. We found large rearrangements in 13 families, and point mutations or microdeletions/insertions in 74 families. The 13 large rearrangements included nine exon deletions, of which at least eight were distinct, two were distinct exon duplications, and two were rearrangements whose precise nature could not be determined. We confirmed that exon 4 is particularly prone to rearrangements. Thirty-six mutations were unreported, and included 10 microdeletions/insertions, 10 missense, five nonsense, eight splicing, and three splicing or missense mutations. Moreover, we detected six novel uncharacterized sequence variants (USV). RT-PCR studies showed that in addition to several intronic splice site mutations tested, the exonic mutations c.882C>G and c.884T>G, located near the 3' end of exon 5, also produced exon skipping. This is the first evidence of SERPING1/C1NH mutations in coding regions that differ from the canonical splice sites that affect splicing, which suggests the presence of an exonic splicing enhancer (ESE) in exon 5.
authors.affiliation: Unidad de Inmunología, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Roche
authors.forename: Alvaro
authors.initials: A
authors.lastname: Blanch
authors.forename: Christiane
authors.initials: C
authors.lastname: Duponchel
authors.forename: Gumersindo
authors.initials: G
authors.lastname: Fontán
authors.forename: Mario
authors.initials: M
authors.lastname: Tosi
authors.forename: Margarita
authors.initials: M
authors.lastname: López-Trascasa
mesh_terms: D017398:Alternative Splicing; D000799:Angioedema / Q000235:genetics; D003174:Complement C1 Inactivator Proteins / Q000235:genetics*; D050718:Complement C1 Inhibitor Protein; D004742:Enhancer Elements, Genetic; D005091:Exons; D005192:Family Health; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics*; D013030:Spain
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; C469952:SERPING1 protein, human; D015843:Serpins