Novel fibrinogen gamma-chain mutation p.Asp342Asn (fibrinogen Pisa) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia
Poster
Data di Pubblicazione:
2013
Citazione:
Novel fibrinogen gamma-chain mutation p.Asp342Asn (fibrinogen Pisa) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia / M. Robusto, P. Braidotti, S. Nastasio, G. Maggiore, F. Peyvandi, R. Asselta, S. Duga. - In: JOURNAL OF THROMBOSIS AND HAEMOSTASIS. - ISSN 1538-7933. - 11:Supplement 2(2013), pp. 717-717. (Intervento presentato al 24. convegno Congress of the International Society on Thrombosis and Haemostasis tenutosi a Amsterdam nel 2013) [10.1111/jth.12284].
Abstract:
Background: Type I fibrinogen deficiencies (hypofibrinogenemia and
afibrinogenemia) are rare congenital disorders characterized by low or
unmeasurable plasma fibrinogen antigen levels. Their genetic bases are
represented by mutations within the three fibrinogen genes, FGA,
FGB, and FGG, coding for Aalpha, Bbeta, and gamma fibrinogen
chains. So far, about 130 genetic defects have been reported to cause
a- or hypofibrinogenemia, but only four mutations, all located in the
fibrinogen gamma-chain gene, were shown to cause hepatic endoplasmic
reticulum storage disease (ERSD).
Aims: To find the genetic basis of hypofibrinogenemia and to investigate
the possibility of hepatic fibrinogen storage disease in a 4-year-old
female with elevated serum aminotransferases.
Methods: Plasma functional and antigen fibrinogen levels were measured
by an assay based on fibrin polymerisation time and by an
enzyme-linked immunosorbent assay, respectively. Mutational screening
was performed by direct sequencing of PCR products covering the
coding sequence of FGA, FGB, and FGG genes. Liver histology was
evaluated by light microscopy and immunocytochemistry.
Results: The proband had concordantly reduced functional and immunologic
fibrinogen levels (136 and 117 mg/dL, respectively), distinctive
of hypofibrinogenemia. Molecular screening revealed the presence of a
novel heterozygous transition (c.1024G>A) in exon 8 of FGG, leading
to the p.Asp342Asn missense mutation (p.Asp316Asn, according to
the mature protein numbering). This non-conservative amino acid substitution
involves a highly conserved residue located in the C-terminal
globular D-domain of the gamma chain. The same mutation was
found also in the proband’s mother and grandfather, who also had
similarly reduced plasma fibrinogen levels but no sign of liver disease.
Histological analysis of hematoxylin-eosin stained sections of proband
liver biopsy samples revealed hepatocyte cytoplasmic microvescicular
steatosis and the presence of small globular and needle-like inclusions.
These inclusions were negative with PAS-D and iron histochemical
reactions, not refracting with polarized light and not auto fluorescent.
All cytoplasmic inclusions of hepatocytes were strongly immunoreactive
with anti-fibrinogen antibody.
Conclusions: This work reports the identification of the fifth mutation
in the FGG gene leading to hypofibrinogenemia and liver ERSD. As
described in other families, our data confirm that the link between the FGG mutation and ERSD is not as strong as that with hypofibrinogenemia.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
M. Robusto, P. Braidotti, S. Nastasio, G. Maggiore, F. Peyvandi, R. Asselta, S. Duga
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