A novel missense mutation in the FGB gene (p.Gly302Arg) leading to afibrinogenemia. Predicted structure and function consequences.
Afibrinogenemia represents the rarest form of fibrinogen deficiency. Causative missense mutations occur rarely and may improve the understanding of fibrinogen structure and function.


METHODS
The propositus was a 26-year-old Argentinian with afibrinogenemia. FGA, FGB and FGG exons and flanking regions were screened by sequencing and the mutant protein was analyzed in silico.


RESULTS
A novel missense mutation in the FGB gene (Bbeta Gly272Arg, p.Gly302Arg) was identified. In silico analysis revealed its location in a highly conserved region, which preserves the core fold of the C-terminal beta-chain and is important for proper secretion. A substitution by a positively charged large Arg residue in this area would most likely disturb the core fold by additional interactions with adjacent residues (p.Asp291, p.Asp297, p.Asp311), or by forming of non-native interactions with other proteins, thereby hindering the action of molecular chaperones. Both alternatives would disturb the regular secretion of the beta-chain.


CONCLUSIONS
The novel missense mutation in the FGB gene causes afibrinogenemia most probably by affecting the secretion of the fibrinogen beta-chain.
Vytautas Ivaškevičius, Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn Sigmund-Freud-Str. 25, 53127 Bonn, Germany, Tel. +49/(0)228/28 71-51 75, Fax -43 20, Email: vytautas.ivaskevicius@ukb.uni-bonn.de.
V
V
Ivaškevičius
H
H
Rühl
G
G
Detarsio
A
A
Biswas
S
S
Gupta
M
M
Davoli
A
A
Quartara
S
S
Pérez
M
M
Raviola
J
J
Oldenburg
D000328:Adult; D000347:Afibrinogenemia / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics*; D003937:Diagnosis, Differential; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006470:Hemorrhage / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D035583:Rare Diseases / Q000175:diagnosis / Q000235:genetics; D013329:Structure-Activity Relationship
D018389:Codon, Nonsense; C000592498:FGB protein, human; D005340:Fibrinogen
Afibrinogenemia; FGA; FGB; FGG; Fibrinogen; bleeding