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Thromb Haemost 1993; 69(03): 217-220
DOI: 10.1055/s-0038-1651583
Original Article
Coagulation
Schattauer GmbH Stuttgart

Paris I Dysfibrinogenemia: A Point Mutation in Intron 8 Results in Insertion of a 15 Amino Acid Sequence in the Fibrinogen γ-Chain

Jonathan B Rosenberg
1   The University of Wisconsin-Milwaukee, Dept. of Health Sciences, Milwaukee, WI, USA
,
Peter J Newman
2   The Blood Research Institute of the Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA
3   The Medical College of Wisconsin, Dept. of Cellular Biology and Anatomy, Milwaukee, WI, USA
,
Michael W Mosesson
4   The University of Wisconsin Medical School, Dept. of Medicine, Milwaukee Clinical Campus, Sinai-Samaritan Medical Center, Milwaukee, WI, USA
,
Marie-Claude Guillin
5   The Laboratoire de Récherche sur I’Hémostase et la Thrombose, Faculté Xavier Bichat, Paris, France
,
David L Amrani
1   The University of Wisconsin-Milwaukee, Dept. of Health Sciences, Milwaukee, WI, USA
› Author Affiliations
Further Information

Publication History

Received 24 July 1992

Accepted after revision 26 October 1992

Publication Date:
05 July 2018 (online)

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Summary

Paris I dysfibrinogenemia results in the production of a fibrinogen molecule containing a functionally abnormal γ-chain. We determined the basis of the molecular defect using polymerase chain reaction (PCR) to amplify the γ-chain region of the Paris I subject’s genomic DNA. Comparative sequence analysis of cloned PCR segments of normal and Paris I genomic DNA revealed only an A→G point mutation occurring at nucleotide position 6588 within intron 8 of the Paris I γ-chain gene. We examined six normal individuals and found only normal sequence in this region, indicating that this change is not likely to represent a normal polymorphism. This nucleotide change leads to a 45 bp fragment being inserted between exons 8 and 9 in the mature γparis I chain mRNA, and encodes a 15 amino acid insert after γ350 [M-C-G-E-A-L-P-M-L-K-D-P-C-Y]. Alternative splicing of this region from intron 8 into the mature Paris I γ-chain mRNA also results after translation into a substitution of S for G at position γ351. Biochemical studies of 14C-iodoacetamide incorporation into disulfide-reduced Paris I and normal fibrinogen corroborated the molecular biologic predictions that two additional cysteine residues exist within the γpariS I chain. We conclude that the insertion of this amino acid sequence leads to a conformationallyaltered, and dysfunctional γ-chain in Paris I fibrinogen.

 

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