title: Novel fibrinogen mutation γ314Thr→Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia.
abstract: Mutation in fibrinogen genes may lead to quantitative or qualitative disorders that result in bleeding, thrombosis or hepatic fibrinogen storage disease. Only three mutations in the fibrinogen γ gene have been identified that cause hepatic endoplasmic reticulum storage of mutant fibrinogen. To investigate the possibility of hepatic fibrinogen storage disease in a 4-year-old male with persistently elevated serum aminotransferases and preserved synthetic function except for a prolonged INR. After informed consent, liver and blood samples were obtained. Liver sections were examined by light microscopy, anti-fibrinogen immunolabelling and electron microscopy. Purified fibrinogen was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and reverse phase high performance liquid chromatography; DNA sequencing was performed using a BigDye Terminator (v. 3.1) cycle sequencing kit. Four-year-old male with persistently elevated transaminases with an INR 1.5 but otherwise normal synthetic function. Fibrinogen activity and thrombin clotting time were abnormal at 0.47 g/L and 46 s respectively. Hepatic histological examination revealed portal inflammatory infiltrates with bridging fibrosis. Clumped eosinophilic material was observed in hepatocytes that was immunoreactive to fibrinogen antisera. Ultrastructural examination showed cytoplasmic inclusions arrayed in fingerprint-like patterns. DNA sequence analysis revealed heterozygosity for a novel γ314Thr →Pro mutation (fibrinogen AI duPont) in the fibrinogen γ gene. Protein analyses showed normal patterns of Aα, Bβ and γ chains suggesting that the variant γ allele was not expressed in plasma fibrinogen. We describe only the fourth mutation to be identified, γ314Thr→Pro (fibrinogen AI duPont), giving rise to hypofibrinogenaemia and hepatic fibrinogen storage disease.
authors.affiliation: Molecular Pathology Laboratory, Christchurch School of Medicine University of Otago, Christchurch, New Zealand.
authors.forename: Stephen O
authors.initials: SO
authors.lastname: Brennan
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Davis
authors.forename: Katrina
authors.initials: K
authors.lastname: Conard
authors.forename: Anthony
authors.initials: A
authors.lastname: Savo
authors.forename: Katryn N
authors.initials: KN
authors.lastname: Furuya
mesh_terms: D000347:Afibrinogenemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D019934:International Normalized Ratio; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D015415:Biomarkers; C027539:fibrinopeptides gamma; D005340:Fibrinogen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase