title: Impaired production of both normal and mutant C1 inhibitor proteins in type I hereditary angioedema with a duplication in exon 8.
abstract: In the autosomal dominant disorder type I hereditary angioedema, reduced levels of C1 inhibitor may be due in part to increased turnover and decreased synthesis of normal C1 inhibitor protein. A type I hereditary angioedema patient was recently described in whom the C1 inhibitor mutation consisted of a 20-bp duplication of nucleotides 1414 to 1433 in exon 8 that introduced a frame shift predicting the loss of a normal stop codon and the translation of a protein 52 amino acids longer than normal. In this study, we analyzed the expression of C1 inhibitor in fibroblasts obtained from a skin biopsy of this patient. Two proteins of approximately 78 and 94 kDa were found intracellularly, corresponding to the products of normal and mutated alleles, respectively. Pulse-chase analysis showed a complete lack of secretion of the mutated form. In addition, there was decreased extracellular production of the normal C1 inhibitor, suggesting either decreased secretion or increased intracellular catabolism of the normal protein because of the presence of the mutant allele. The production of other complement proteins was normal. This study provides a model for further analysis of autosomal dominant genetic disorders in which production of the functional protein may be affected by the product of the mutated allele.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Ernst
authors.forename: A
authors.initials: A
authors.lastname: Circolo
authors.forename: A E
authors.initials: AE
authors.lastname: Davis
authors.forename: K
authors.initials: K
authors.lastname: Gheesling-Mullis
authors.forename: M
authors.initials: M
authors.lastname: Fliesler
authors.forename: R C
authors.initials: RC
authors.lastname: Strunk
mesh_terms: D000483:Alleles; D000581:Amidohydrolases / Q000494:pharmacology; D000799:Angioedema / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D003167:Complement Activation; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015922:Complement C1q / Q000276:immunology; D015923:Complement C1r / Q000276:immunology; D005091:Exons / Q000276:immunology*; D005347:Fibroblasts / Q000378:metabolism; D006596:Hexosaminidases / Q000494:pharmacology; D006801:Humans; D009154:Mutation / Q000276:immunology*; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D003174:Complement C1 Inactivator Proteins; D012333:RNA, Messenger; D015922:Complement C1q; D006596:Hexosaminidases; D015923:Complement C1r; D000581:Amidohydrolases; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase