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Open AccessArticle

A Novel Mutation in the Fibrinogen Bβ Chain (c.490G>A; End of Exon 3) Causes a Splicing Abnormality and Ultimately Leads to Congenital Hypofibrinogenemia

1
Department of Health and Medical Sciences, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
2
Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
3
Department of Laboratory Medicine, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(11), 2470; https://doi.org/10.3390/ijms18112470
Received: 26 October 2017 / Revised: 15 November 2017 / Accepted: 16 November 2017 / Published: 20 November 2017
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
We found a novel heterozygous mutation in the fibrinogen Bβ chain (c.490G>A) of a 3-year-old girl with congenital hypofibrinogenemia. To clarify the complex genetic mechanism, we made a mini-gene including a FGB c.490G>A mutation region, transfected it into a Chinese Hamster Ovary (CHO) cell line, and analyzed reverse transcription (RT) products. The assembly process and secretion were examined using recombinant mutant fibrinogen. Direct sequencing demonstrated that the mutant RT product was 99 bp longer than the wild-type product, and an extra 99 bases were derived from intron 3. In recombinant expression, a mutant Bβ-chain was weakly detected in the transfected CHO cell line, and aberrant fibrinogen was secreted into culture media; however, an aberrant Bβ-chain was not detected in plasma. Since the aberrant Bβ-chain was catabolized faster in cells, the aberrant Bβ-chain in a small amount of secreted fibrinogen may catabolize in the bloodstream. FGB c.490G>A indicated the activation of a cryptic splice site causing the insertion of 99 bp in intron 3. This splicing abnormality led to the production of a Bβ-chain possessing 33 aberrant amino acids, including two Cys residues in the coiled-coil domain. Therefore, a splicing abnormality may cause impaired fibrinogen assembly and secretion. View Full-Text
Keywords: hypofibrinogenemia; FGB; splicing abnormality; cryptic splice site hypofibrinogenemia; FGB; splicing abnormality; cryptic splice site
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Taira, C.; Matsuda, K.; Arai, S.; Sugano, M.; Uehara, T.; Okumura, N. A Novel Mutation in the Fibrinogen Bβ Chain (c.490G>A; End of Exon 3) Causes a Splicing Abnormality and Ultimately Leads to Congenital Hypofibrinogenemia. Int. J. Mol. Sci. 2017, 18, 2470.

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