A classification system for cross-reactive material-negative factor XI deficiency.
The bleeding disorder associated with factor XI (fXI) deficiency is typically inherited as an autosomal recessive trait. However, some fXI mutations may be associated with dominant disease transmission. FXI is a homodimer, a feature that could allow certain mutations to exert a dominant-negative effect on wild-type fXI secretion through heterodimer formation. We describe 2 novel fXI mutations (Ser225Phe and Cys398Tyr) that form intracellular dimers, are secreted poorly, and exhibit dominant-negative effects on wild-type fXI secretion in cotransfection experiments. Available data now suggest that mutations associated with crossreactive material-negative fXI deficiency fall into 1 of 3 mechanistic categories: (1) mutations that reduce or prevent polypeptide synthesis, (2) polypeptides that fail to form intracellular dimers and are retained in cells as monomers, and (3) polypeptides that form dimers that are not secreted. The latter category likely accounts for many cases of dominant disease transmission.
Kravtsov
Dmitri V
DV
Department of Pathology, Vanderbilt University, Nashville, TN 37232-6307, USA.
Monahan
Paul E
PE
Gailani
David
D
D000328:Adult; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005091:Exons; D005172:Factor XI / Q000235:genetics; D005173:Factor XI Deficiency / Q000145:classification* / Q000175:diagnosis*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D014162:Transfection
D010455:Peptides; D004247:DNA; D005172:Factor XI
Br J Haematol. 1988 Aug;69(4):521-8
3408688
Am J Hematol. 1988 May;28(1):8-12
3369441
Biochemistry. 1991 Feb 26;30(8):2056-60
1998667
N Engl J Med. 1991 Jul 18;325(3):153-8
2052060
Biochemistry. 1991 Oct 29;30(43):10363-70
1931959
Blood. 1992 Mar 15;79(6):1435-40
1547342
Biochemistry. 1992 May 19;31(19):4680-4
1581318
Blood. 1997 Oct 1;90(7):2654-9
9326232
Hum Gene Ther. 1998 Oct 10;9(15):2263-75
9794210
AMA Arch Intern Med. 1957 Aug;100(2):232-40
13443544
Blood. 1961 Aug;18:149-65
13739555
J Biol Chem. 1999 Dec 17;274(51):36373-8
10593931
Br J Haematol. 1999 Dec;107(4):763-5
10606881
Blood. 2000 Feb 15;95(4):1336-41
10666208
Blood. 2001 Nov 15;98(10):2973-9
11698279
Blood. 2004 Jul 1;104(1):128-34
15026311
J Biol Chem. 1977 Sep 25;252(18):6432-7
893417
J Lab Clin Med. 1985 Dec;106(6):718-22
4067382
Proc Natl Acad Sci U S A. 1989 Oct;86(20):7667-71
2813350