Semin Thromb Hemost 2000; Volume 26(Number 01): 005-010
DOI: 10.1055/s-2000-9795
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4663

Molecular and Genetic Mechanisms of Factor XIII A Subunit Deficiency

Akitada Ichinose, Masayoshi Souri, Tomonori Izumi, Nobumasa Takahashi
  • Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan. Supported in part by research grants from the Ministry of Education, Science and Culture, Japan (08457271), the Naito Foundation (Japan), and the Japan Research Foundation for Clinical Pharmacology.
Further Information

Publication History

Publication Date:
31 December 2000 (online)

 

ABSTRACT

Factor XIII is a proenzyme for a plasma transglutaminase. Factor XIII in plasma is a tetramer (A2B2) held together by noncovalent bonds, and the A subunit contains the active site. Recently, the three-dimensional structure of the A subunit has been determined by x-ray crystallography. To understand the structure-function relationships of the factor XIII molecule and its clinical implications in factor XIII deficiency, we characterized its genetic defects and closely examined its gene products, including mRNA and protein levels. A variety of missense and nonsense mutations (Arg260-Cys, Tyr283-Cys, Gly562-Arg) and deletions/insertions with or without out-of-frame shift/premature termination and splicing abnormalities (4-bp deletion with 464Stop, T insertion at the exon IV/intron D boundary with exon IV-skipping, 20-bp deletion at the exon I/intron A boundary) has been identified in cases demonstrating A subunit deficiency. In some cases, the A subunit mRNA levels were severely reduced. Their molecular and cellular bases have also been explored by expression experiments in mammalian cells and by molecular modeling. In most cases, impaired folding and/or conformational changes of the mutant A subunits lead to both intra- and extracellular instability, which is responsible for the A subunit deficiency in the patients.

KEYWORD

Transglutaminase - cross-linking - bleeding disorder - wound healing - molecular abnormality

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