title: Characterisation of a new C1 inhibitor mutant in a patient with hepatocellular carcinoma.
abstract: A patient developed the first case of hepatocarcinoma associated with hereditary angioedema within the context of a 13-year long prophylactic danazol exposure. We sought to identify the molecular defect and to test the relative contribution to the development of hepatocarcinoma of intracellular accumulation of abnormal C1 inhibitor (C1-INH) protein. The de novo mutation c.878_881delTCTA was identified, leading to a premature stop codon. Monocyte C1-INH secretions of the patient and of her affected daughter were, respectively, 26 and 18% compared to controls. Mutant transcripts compatible with the 4bp deletion were detectable as a faint RT-PCR product both in interferon-stimulated monocytes and in liver tissue, whereas total C1-INH mRNA was found nearly half the amount recovered from normal subjects. In order to study the consequences at the protein level of the low expression of the mutant allele, we analysed the intracellular fate of mutant products. COS-7 cells were transiently transfected with a C1-INH expression minigene encoding the mutant protein. In pulse-chase experiments, a faint 75,000-M(r) band was detected only within 10min. Both the c.878_881delTCTA mutant transcript and the intracellular abnormal C1-INH protein are unstable. Our data therefore rule out the hypothesis of an accumulation of the mutant protein at levels relevant for the pathology and strengthen the link between the development of hepatocarcinoma and danazol exposure.
authors.affiliation: INSERM U607 and Laboratoire de Biochimie Génétique et Moléculaire, CHU de Grenoble, F-38043 Grenoble, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Denise
authors.initials: D
authors.lastname: Ponard
authors.forename: Christiane
authors.initials: C
authors.lastname: Duponchel
authors.forename: Françoise
authors.initials: F
authors.lastname: Csopaki
authors.forename: Laurence
authors.initials: L
authors.lastname: Bouillet
authors.forename: Mario
authors.initials: M
authors.lastname: Tosi
authors.forename: Joel
authors.initials: J
authors.lastname: Lunardi
authors.forename: Christian
authors.initials: C
authors.lastname: Drouet
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000799:Angioedema / Q000188:drug therapy*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D002522:Chlorocebus aethiops; D018388:Codon, Terminator; D003174:Complement C1 Inactivator Proteins / Q000235:genetics* / Q000378:metabolism; D050718:Complement C1 Inhibitor Protein; D003613:Danazol / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes; D010375:Pedigree; D015843:Serpins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018388:Codon, Terminator; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; C469952:SERPING1 protein, human; D015843:Serpins; D003613:Danazol