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The Clinical Spectrum of Leukocyte Adhesion Deficiency (LAD) III due to Defective CalDAG-GEF1

Abstract

Introduction

Leukocyte adhesion deficiency (LAD) type III is a rare syndrome characterized by severe recurrent infections, leukocytosis, and increased bleeding tendency. All integrins are normally expressed yet a defect in their activation leads to the observed clinical manifestations.

Materials and Methods

Less than 20 patients have been reported world wide and the primary genetic defect was identified in some of them. Here we describe the clinical features of patients in whom a mutation in the calcium and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CalDAG GEF1) was found and compare them to other cases of LAD III and to animal models harboring a mutation in the CalDAG GEF1 gene.

Discussion

The hallmarks of the syndrome are recurrent infections accompanied by severe bleeding episodes distinguished by osteopetrosis like bone abnormalities and neurodevelopmental defects.

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References

  1. Etzioni A, Harlan JM. Cell adhesion and leukocyte adhesions defects. In: Smith EM, Puck J, Ochs HD eds. Primary Immune deficiency disease. A molecular and genetic approach, 2nd ed. Oxford University Press; 2007. p. 550–64.

  2. Hogg N, Stewart MP, Scarth SL, Newton R, Shaw JM, Law SK, et al. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins MAC-1 and LFA-1. J Clin Invest 1999;103:97–106. doi:10.1172/JCI3312.

    PubMed  Article  CAS  Google Scholar 

  3. Etzioni A, Frydman M, Pollack S, Avidor I, Phillips ML, Paulson JC, et al. Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med 1992;327:1789–92.

    PubMed  CAS  Google Scholar 

  4. Lubke T, Marquardt T, Etzioni A, Hatmann E, von Figura K, Korner C. Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 2001;28:73–6. doi:10.1038/88299.

    PubMed  Article  CAS  Google Scholar 

  5. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–14. doi:10.1016/0092-8674(94)90337-9.

    PubMed  Article  CAS  Google Scholar 

  6. McDowall A, Inwald D, Leitinger B, Jones A, Liesner R, Klein N, et al. A novel form of integrin dysfunction involving beta 1, beta 2 and beta 3 integrings. J Clin Invest 2003;111:51–60.

    PubMed  CAS  Google Scholar 

  7. Harris ES, Shigeoka AO, Li W, Adams RH, Prescott SM, McIntyre TM, et al. A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta 1 and beta 2 integrins. Blood 2001;97:767–76. doi:10.1182/blood.V97.3.767.

    PubMed  Article  CAS  Google Scholar 

  8. Alon R, Aker M, Feigelson S, Sokolowsky-Eisenberg M, Stauton D, Cinamon G, et al. A novel genetic leukocyte adhesion deficiency in sub-second triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow. Blood 2003;101:4437–45.

    PubMed  Article  CAS  Google Scholar 

  9. Alon R, Etzioni A. Lad III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol 2003;24:561–6. doi:10.1016/j.it.2003.08.001.

    PubMed  Article  CAS  Google Scholar 

  10. Kinashi T. intracellular signaling controlling integrin activation in lymphocytes. Nat Rev Immunol 2005;5:546–59. doi:10.1038/nri1646.

    PubMed  Article  CAS  Google Scholar 

  11. Pasvolsky R, Felgelson SW, Kilic SS, Simon AJ, Tal-Lapidot G, Grabovsky V, et al. LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEF1 in lymphocyted, neutrophils and platelets. J Exp Med 2007;204:1571–82.

    PubMed  CAS  Google Scholar 

  12. Ginsberg MH, Partridge A, Shattil SJ. Integrinregulation. Curr Opin Cell Biol 2005;17:509–16. doi:10.1016/j.ceb.2005.08.010.

    PubMed  Article  CAS  Google Scholar 

  13. Nurden P, Nurden AT. Congenital disorders associated with platelets dysfunctions. Thromb Haemost 2008;99:253–63.

    PubMed  CAS  Google Scholar 

  14. Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, et al. CalDAG GEF1 integrates signaling for platelet aggregation and thrombus formation. Nat Med 2004;10:982–6. doi:10.1038/nm1098.

    PubMed  Article  CAS  Google Scholar 

  15. Kuijpars TW, van Brudden R, Kamerbeek N, Tool ATJ, Hicsonmez G, Gurgey A, et al. Natural history and early diagnosis of LAD-1/variant. Blood 2007;109:3529–37. doi:10.1182/blood-2006-05-021402.

    Article  Google Scholar 

  16. Kawasaki H, Springett GM, Toki S, Canales JJ, Harlan P, Blumenstiel JP, et al. A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. Proc Natl Acad Sci U S A 1998;95:13278–83. doi:10.1073/pnas.95.22.13278.

    PubMed  Article  CAS  Google Scholar 

  17. Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, et al. Osteoclast poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Gen 2007;39:960–2.

    Article  CAS  Google Scholar 

  18. Teitelbaum SL. Osteoclasts:What do they do and how do they do it? Am J Pathol 2007;170:427–35. doi:10.2353/ajpath.2007.060834.

    PubMed  Article  CAS  Google Scholar 

  19. Bergmeier W, George T, Wang HW, Crittenden JR, Baldwin ACW, Cifuni SM, et al. Mice lacking the signaling molecule CalDAG-GEF1 present a model for leukocyte adhesion deficiency type III. J Clin Invest 2007;117:1699–707. doi:10.1172/JCI30575.

    PubMed  Article  CAS  Google Scholar 

  20. Boudreaux MK, Schmutz SM, French PS. Calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEF1) gene mutations in a thrombopathic Simmental calf. Vet Pathol 2007;44:932–5. doi:10.1354/vp.44-6-932.

    PubMed  Article  CAS  Google Scholar 

  21. Boudreaux MK, Catalfamo JL, Klok M. Calcium in factor I gene mutations associated with loss of function in canine platelets. Trans Res 2007;150:81–92. doi:10.1016/j.trsl.2007.03.006.

    Article  CAS  Google Scholar 

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Acknowledgement

We would like to thank Prof. Alon for critically reviewing the paper and to Prof. Rechavi’s group for helping in the genetic analysis of the families.

Recently we found that these patients have also mutation in Kindlin 3 (Blood Accepted).

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Correspondence to Amos Etzioni.

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Kilic, S.S., Etzioni, A. The Clinical Spectrum of Leukocyte Adhesion Deficiency (LAD) III due to Defective CalDAG-GEF1. J Clin Immunol 29, 117–122 (2009). https://doi.org/10.1007/s10875-008-9226-z

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  • DOI: https://doi.org/10.1007/s10875-008-9226-z

Keywords

  • Leukocytes
  • platelets
  • integrins
  • adhesion
  • infections
  • bleeding
  • immunodeficiency