SEARCH:   Advanced

Blood, 7 May 2009, Vol. 113, No. 19, pp. 4740-4746. Prepublished online as a Blood First Edition Paper on December 8, 2008; DOI 10.1182/blood-2008-10-182154. This Article Full Text (PDF) All Versions of this Article: blood-2008-10-182154v1 113/19/4740    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuijpers, T. W. Articles by Baas, F. Search for Related Content PubMed PubMed Citation Articles by Kuijpers, T. W. Articles by Baas, F. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 2, 2008 Accepted December 1, 2008 LAD-1/variant syndrome is caused by mutations in FERMT3 Taco W. Kuijpers*, Edith van de Vijver, Marian A.J. Weterman, Martin de Boer, Anton T.J. Tool, Timo K. van den Berg, Markus Moser, Marja E Jakobs, Karl Seeger, Ozden Sanal, Sule Unal, Mualla Cetin, Dirk Roos, Arthur J Verhoeven, and Frank Baas Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, Netherlands Department of Neurogenetics, Genetic Core Facility, AMC, University of Amsterdam, Amsterdam, Netherlands Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany Department of Pediatric Oncology/Hematology, Otto-Heubner-Center for Pediatric and Adolescent Medicine, Charite-Universitatstmedizin, Berlin, Germany Pediatric Immunology Unit, Hacettepe University, Ankara, Turkey Pediatric Hematology Unit, Hacettepe University, Ankara, Turkey * Corresponding author; email: t.w.kuijpers{at}amc.uva.nl. Leukocyte Adhesion Deficiency-1/variant (LAD1v) syndrome presents early in life and manifests by infections without pus formation in the presence of a leukocytosis combined with a Glanzmann-type bleeding disorder, due to a hematopoietic defect in integrin activation. In 7 consanguineous families, we previously established that this defect was not due to defective Rap1 activation as proposed by other investigators. In search of the genetic defect, we carried out homozygosity mapping in 3 of these patients, and a 13-Mb region on chromosome 11 was identified. All 7 LAD1v families share the same haplotype, in which three disease-associated sequence variants were identified: a putative splice site mutation in CALDAGGEF1 (encoding an exchange factor for Rap1), an intronic 1.8-kb deletion in NRXN2 and a premature stopcodon (p.Arg509X) in FERMT3. Two other LAD1v patients were found to carry different stopcodons in FERMT3 (p.Arg573X and p.Trp229X) and lacked the CALDAGGEF1 and NRXN2 mutations, providing convincing evidence that FERMT3 is the gene responsible for LAD1v. FERMT3 encodes kindlin-3 in hematopoietic cells, a protein present together with integrins in focal adhesions. Kindlin-3 protein expression was undetectable in the leukocytes and platelets of all patients tested. These results indicate that LAD-1/variant syndrome is caused by truncating mutations in FERMT3. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: LAD syndromes: FERMT3 kindles the signal Guy A. Zimmerman Blood 2009 113: 4485-4486. [Full Text] [PDF] This article has been cited by other articles: C. Has, C. Herz, E. Zimina, H.-Y. Qu, Y. He, Z.-G. Zhang, T.-T. Wen, Y. Gache, M. Aumailley, and L. Bruckner-Tuderman Kindlin-1 Is Required for RhoGTPase-Mediated Lamellipodia Formation in Keratinocytes Am. J. Pathol., October 1, 2009; 175(4): 1442 - 1452. [Abstract] [Full Text] [PDF] J. E. Lai-Cheong, M. Parsons, A. Tanaka, S. Ussar, A. P. South, S. Gomathy, J. B. Mee, J.-B. Barbaroux, T. Techanukul, N. Almaani, et al. Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation Am. J. Pathol., October 1, 2009; 175(4): 1431 - 1441. [Abstract] [Full Text] [PDF] E. Manevich-Mendelson, S. W. Feigelson, R. Pasvolsky, M. Aker, V. Grabovsky, Z. Shulman, S. S. Kilic, M. A. Rosenthal-Allieri, S. Ben-Dor, A. Mory, et al. Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions Blood, September 10, 2009; 114(11): 2344 - 2353. [Abstract] [Full Text] [PDF] G. A. Zimmerman LAD syndromes: FERMT3 kindles the signal Blood, May 7, 2009; 113(19): 4485 - 4486. [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020