|
|
Blood, 1 March 2006, Vol. 107, No. 5, pp. 1903-1907.
Prepublished online as a Blood First Edition Paper on November 22, 2005January 31, 2006; DOI 10.1182/blood-2005-09-3620.
 Previous Article | Next Article 
Submitted September 9, 2005
Accepted October 13, 2005
Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2
Bin Zhang, Beth McGee, Jennifer S Yamaoka, Hugo Guglielmone, Katharine A Downes, S Minoldo, G Jarchum, Flora Peyvandi, Norma B de Bosch, Arlette Ruiz-Saez, Bernard Chatelain, Marian Olpinski, Paula Bockenstedt, Wolfgang Sperl, Randal J Kaufman, William C Nichols, Tuddenham EGD, and David Ginsburg*
Life Sciences Institute, Departments of Internal Medicine, Human Genetics, Biological Chemistry and Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
Sercicio de Hematologia, Clinica-CIBICI-CONICET, UNC, Cordoba, Argentina
Case Western Reserve University, University Hospitals of Cleveland, Cleveland, USA
Bonomi Haemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milano, Milano, Italy
Centro Nacional de Hemofilia, Banco Municipal de Sangre, Caracas, Venezuela
Universite Catholique de Louvain, University Hospital of Mont-Godinne, Belgium
Institute of Nursing and Midwifery, University of Rzeszow, Poland
Department of Pediatrics, Private Medical University, Salzburg, Austria
Cincinnati Children's Hospital Medical Center, Cincinnati, USA
MRC Clinical Sciences Center, Imperial College, London, United Kingdom
* Corresponding author; email: ginsburg{at}umich.edu.
Mutations in LMAN1 (ERGIC-53) or MCFD2 cause combined deficiency of factor V and factor VIII (F5F8D). LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi. In this study, we analyzed 10 previously reported and 9 new F5F8D families. Mutations in the LMAN1 or MCFD2 genes accounted for 14 of these families, including 3 alleles resulting in no LMAN1 mRNA accumulation. Combined with our previous reports, we have identified LMAN1 or MCFD2 mutations as the causes of F5F8D in 70 of 75 families. Among the 5 families in which no mutations were identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Our results suggest that mutations in LMAN1 and MCFD2 may account for all cases of F5F8D. Immunoprecipitation and Western blot analysis detected a low level of LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense mutations in LMAN1 (C475R) or MCFD2 (I136T), suggesting that complete loss of the complex may not be required for clinically significant reduction in FV and FVIII.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
B. Zhang, M. Spreafico, C. Zheng, A. Yang, P. Platzer, M. U. Callaghan, Z. Avci, N. Ozbek, J. Mahlangu, T. Haw, et al.
Genotype-phenotype correlation in combined deficiency of factor V and factor VIII
Blood,
June 15, 2008;
111(12):
5592 - 5600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Kawasaki, Y. Ichikawa, I. Matsuo, K. Totani, N. Matsumoto, Y. Ito, and K. Yamamoto
The sugar-binding ability of ERGIC-53 is enhanced by its interaction with MCFD2
Blood,
February 15, 2008;
111(4):
1972 - 1979.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Nyfeler, Y. Kamiya, F. Boehlen, K. Yamamoto, K. Kato, P. de Moerloose, H.-P. Hauri, and M. Neerman-Arbez
Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency
Blood,
February 1, 2008;
111(3):
1299 - 1301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. M. Olkkonen and E. Ikonen
When intracellular logistics fails - genetic defects in membrane trafficking
J. Cell Sci.,
December 15, 2006;
119(24):
5031 - 5045.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
