title: Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature.
abstract: BACKGROUND
  Fibrinogen storage disease (FSD) is characterized by hypofibrinogenemia and hepatic inclusions due to impaired release of mutant fibrinogen which accumulates and aggregates in the hepatocellular endoplasmic reticulum. Liver disease is variable.
  
  
  OBJECTIVE
  We studied a new Swiss family with fibrinogen Aguadilla. In order to understand the molecular peculiarity of FSD mutations, fibrinogen Aguadilla and the three other causative mutations, all located in the γD domain, were modelled.
  
  
  METHODS
  The proband is a Swiss girl aged 4 investigated because of fatigue and elevated liver enzymes. Protein structure models were prepared using the Swiss-PdbViewer and POV-Ray software.
  
  
  RESULTS
  The proband was found to be heterozygous for fibrinogen Aguadilla: FGG Arg375Trp. Familial screening revealed that her mother and maternal grandmother were also affected and, in addition, respectively heterozygous and homozygous for the hereditary haemochromatosis mutation HFE C282Y. Models of backbone and side-chain interactions for fibrinogen Aguadilla in a 10-angstrom region revealed the loss of five H-bonds and the gain of one H-bond between structurally important amino acids. The structure predicted for fibrinogen Angers showed a novel helical structure in place of hole 'a' on the outer edge of γD likely to have a negative impact on fibrinogen assembly and secretion.
  
  
  CONCLUSIONS
  The mechanism by which FSD mutations generate hepatic intracellular inclusions is still not clearly established although the promotion of aberrant intermolecular strand insertions is emerging as a likely cause. Reporting new cases is essential in the light of novel opportunities of treatment offered by increasing knowledge of the degradation pathway and autophagy.
authors.affiliation: Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Casini
authors.affiliation: Paediatric Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sokollik
authors.affiliation: Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
authors.forename: S W
authors.initials: SW
authors.lastname: Lukowski
authors.affiliation: Paediatric Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Inselspital, University of Bern, Bern, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Lurz
authors.affiliation: Division of Human Genetics, Department of Paediatrics, Inselspital, Bern, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Rieubland
authors.affiliation: Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: de Moerloose
authors.affiliation: Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.|Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Neerman-Arbez
mesh_terms: D000293:Adolescent; D000328:Adult; D000347:Afibrinogenemia / Q000150:complications* / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D055815:Young Adult
chemical_list: D005340:Fibrinogen
keywords: congenital fibrinogen disorders; genetics; hypofibrinogenemia; liver disease; molecular models; mutation