Abstract | BACKGROUND: Quantitative fibrinogen deficiencies (hypofibrinogenemia and afibrinogenemia) are rare congenital disorders characterized by low/unmeasurable plasma fibrinogen antigen levels. Their genetic basis is invariably represented by mutations within the fibrinogen genes (FGA, FGB and FGG coding for the Aα, Bβ and γ chains). Currently, only four mutations (p.Gly284Arg, p.Arg375Trp, delGVYYQ 346-350, p.Thr314Pro), all affecting the fibrinogen γ chain, have been reported to cause fibrinogen storage disease (FSD), a disorder characterized by protein aggregation, endoplasmic reticulum retention and hypofibrinogenemia. OBJECTIVES: To investigate the genetic basis of FSD in two hypofibrinogenemic patients. METHODS: The mutational screening of the fibrinogen genes was performed by direct DNA sequencing. The impact of identified mutations on fibrinogen structure was investigated by in-silico molecular modeling. Liver histology was evaluated by light microscopy, electron microscopy and immunocytochemistry. RESULTS: Here, we describe two hypofibrinogenemic children with persistent abnormal liver function parameters. Direct sequencing of the coding portion of fibrinogen genes disclosed two novel FGG missense variants (p.Asp316Asn, fibrinogen Pisa; p.Gly366Ser, fibrinogen Beograd), both present in the heterozygous state and affecting residues located in the fibrinogen C-terminal γ-module. Liver sections derived from biopsies of the two patients were examined by immunocytochemical analyses, revealing hepatocyte cytoplasmic inclusions immunoreactive to anti- fibrinogen antibodies. CONCLUSIONS: Our work strongly confirms the clustering of mutations causing FSD in the fibrinogen γ chain between residues 284 and 375. Based on an in-depth structural analysis of all FSD-causing mutations and on their resemblance to mutations leading to serpinopathies, we also comment on a possible mechanism explaining fibrinogen polymerization within hepatocytes.
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Authors | R Asselta, M Robusto, P Braidotti, F Peyvandi, S Nastasio, L D'Antiga, V N Perisic, G Maggiore, S Caccia, S Duga |
Journal | Journal of thrombosis and haemostasis : JTH
(J Thromb Haemost)
Vol. 13
Issue 8
Pg. 1459-67
(Aug 2015)
ISSN: 1538-7836 [Electronic] England |
PMID | 26039544
(Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2015 International Society on Thrombosis and Haemostasis. |
Chemical References |
- Fibrinogens, Abnormal
- fibrinogen Beograd
- fibrinogen Pisa
- fibrinopeptides gamma
- Fibrinogen
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Topics |
- Afibrinogenemia
(diagnosis, genetics, metabolism)
- Amino Acid Sequence
- Child, Preschool
- DNA Mutational Analysis
- Female
- Fibrinogen
(chemistry, genetics, metabolism)
- Fibrinogens, Abnormal
(chemistry, genetics, metabolism)
- Genetic Predisposition to Disease
- Heterozygote
- Humans
- Liver
(metabolism)
- Liver Diseases
(diagnosis, genetics, metabolism)
- Liver Function Tests
- Male
- Models, Molecular
- Molecular Sequence Data
- Mutation, Missense
- Phenotype
- Protein Conformation
- Structure-Activity Relationship
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