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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 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 Citation Map 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 Immunobiology Phagocytes, Granulocytes, and Myelopoiesis Platelets and Thrombopoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS LAD-1/variant syndrome is caused by mutations in FERMT3 Taco W. Kuijpers1,2, Edith van de Vijver1,2, Marian A. J. Weterman3, Martin de Boer2, Anton T. J. Tool2, Timo K. van den Berg2, Markus Moser4, Marja E. Jakobs3, Karl Seeger5, Özden Sanal6, Sule Ünal7, Mualla Çetin7, Dirk Roos2, Arthur J. Verhoeven2, and Frank Baas3 1 Emma Children's Hospital, 2 Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, and 3 Department of Neurogenetics, Genetic Core Facility, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 4 Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany; 5 Department of Pediatric Oncology/Hematology, Otto-Heubner-Center for Pediatric and Adolescent Medicine, Charité-Universitätsmedizin, Berlin, Germany; and 6 Pediatric Immunology Unit and 7 Pediatric Hematology Unit, Hacettepe University, Ankara, Turkey 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, resulting from a hematopoietic defect in integrin activation. In 7 consanguineous families, we previously established that this defect was not the result of 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 3 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 stop codon (p.Arg509X) in FERMT3. Two other LAD1v patients were found to carry different stop codons 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 the LAD1v 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]

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