RGD Reference Report - Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. - Rat Genome Database

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Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites.

Authors: Spena, S  Duga, S  Asselta, R  Malcovati, M  Peyvandi, F  Tenchini, ML 
Citation: Spena S, etal., Blood 2002 Dec 15;100(13):4478-84. Epub 2002 Aug 1.
RGD ID: 737709
Pubmed: PMID:12393540   (View Abstract at PubMed)
DOI: DOI:10.1182/blood-2002-06-1647   (Journal Full-text)

Congenital afibrinogenemia is a rare inherited coagulopathy, characterized by very low or unmeasurable plasma levels of immunoreactive fibrinogen. So far, 25 mutations have been identified in afibrinogenemia, 17 in the Aalpha, 6 in the gamma, and only 2 in the Bbeta fibrinogen-chain genes. Here, 2 afibrinogenemic probands, showing undetectable levels of functional fibrinogen, were screened for causative mutations at the genomic level. Sequence analysis of the 3 fibrinogen genes disclosed 2 novel homozygous mutations in introns 6 and 7 of the Bbeta-chain gene (IVS6 + 13C > T and IVS7 + 1G > T), representing the first Bbeta-chain gene splicing mutations described in afibrinogenemia. The IVS6 + 13C > T mutation predicts the creation of a donor splice site in intron 6, whereas the IVS7 + 1G > T mutation causes the disappearance of the invariant GT dinucleotide of intron 7 donor splice site. To analyze the effect of these mutations, expression plasmids containing Bbeta-chain minigene constructs, either wild-type or mutant, were transfected in HeLa cells. Assessed by semiquantitative analysis of reverse transcriptase-polymerase chain reaction products, the IVS7 + 1G > T mutation resulted in multiple aberrant splicings, while the IVS6 + 13C > T mutation resulted in activation of a new splice site 11 nucleotides downstream of the physiologic one. Both mutations are predicted to determine protein truncations, supporting the importance of the C-terminal domain of the Bbeta chain for fibrinogen assembly and secretion.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
congenital afibrinogenemia  IAGP 737709 RGD 
congenital afibrinogenemia  ISOFGB (Homo sapiens)737709; 737709 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Hypofibrinogenemia  IAGP 737709 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Fgb  (fibrinogen beta chain)

Genes (Mus musculus)
Fgb  (fibrinogen beta chain)

Genes (Homo sapiens)
FGB  (fibrinogen beta chain)


Additional Information