A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family

• Published in: Allergy (Copenhagen) Vol. 66; no. 10; pp. 1384 - 1390
• Main Authors: Ferraro, M. F., Moreno, A. S., Castelli, E. C., Donadi, E. A., Palma, M. S., Arcuri, H. A., Lange, A. P., Bork, K., Sarti, W., Arruda, L. K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2011; Blackwell
• Subjects: Adolescent; Adult; Age of Onset; Aged; Allergic diseases; Allergies; Amino Acid Sequence; angioedema; Angioedemas, Hereditary - genetics; Base Sequence; Biological and medical sciences; Bradykinin; Brazil; C1 inhibitor; Child; Child, Preschool; complement; Complement C1 Inactivator Proteins - genetics; Complement C1 Inactivator Proteins - metabolism; Complement C1 Inhibitor Protein; Complement C4 - metabolism; complement component C1; Cytosine; Dermatology; Edema; Exons; Family Health; Female; Frameshift Mutation; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene deletion; Genes; Genetic disorders; hereditary angioedema; Humans; Immunopathology; Infant; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Mutation; Nonsense mutation; Nucleotides; Pain; Pedigree; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Deletion; serine protease inhibitors; Skin allergic diseases. Stinging insect allergies; Transcription; Young Adult; South America; Brazil; America; Allergy; Skin disease; Complement C1; Peptide hormone; Neuropeptide; Angioneurotic edema; Immunology; Gene; Bradykinin; Cause; Deletion; Family environment; Genetics; complement; Immunopathology; Serine endopeptidases; Enzyme; Dermatology; Family study; C1 inhibitor; Hereditary; Peptidases; hereditary angioedema; Nucleotide; Hydrolases; serine protease inhibitors; Protease inhibitor
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/j.1398-9995.2011.02658.x

To cite this article: Ferraro MF, Moreno AS, Castelli EC, Donadi EA, Palma MS, Arcuri HA, Lange AP, Bork K, Sarti W, Arruda LK. A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family.Allergy 2011; 66: 1384–1390. Background:  Hereditary angioedema is an autosomal dominant disease characterized by episodes of subcutaneous and submucosal edema. It is caused by deficiency of the C1 inhibitor protein, leading to elevated levels of bradykinin. More than 200 mutations in C1 inhibitor gene have been reported. The aim of this study was to analyze clinical features of a large family with an index case of hereditary angioedema and to determine the disease‐causing mutation in this family. Methods:  Family pedigree was constructed with 275 individuals distributed in five generations. One hundred and sixty‐five subjects were interviewed and investigated for mutation at the C1 inhibitor gene. Subjects reporting a history of recurrent episodes of angioedema and/or abdominal pain attacks underwent evaluation for hereditary angioedema. Results:  We have identified a novel mutation at the C1 inhibitor gene, c.351delC, which is a single‐nucleotide deletion of a cytosine on exon 3, resulting in frameshift with premature stop codon. Sequencing analysis of the hypothetical truncated C1 inhibitor protein allowed us to conclude that, if transcription occurs, this protein has no biological activity. Twenty‐eight members of the family fulfilled diagnostic criteria for hereditary angioedema and all of them presented the c.351delC mutation. Variation in clinical presentation and severity of disease was observed among these patients. One hundred and thirty‐seven subjects without hereditary angioedema did not have the c.351delC mutation. Conclusion:  The present study provides definitive evidence to link a novel genetic mutation to the development of hereditary angioedema in patients from a Brazilian family.