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Blood, 1 July 2006, Vol. 108, No. 1, pp. 362-369. Prepublished online as a Blood First Edition Paper on March 14, 2006; DOI 10.1182/blood-2005-11-4377. This Article Full Text (PDF) Supplemental Table and Figure All Versions of this Article: 2005-11-4377v1 108/1/362    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 Jung, J. Articles by Klein, C. Search for Related Content PubMed PubMed Citation Articles by Jung, J. Articles by Klein, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 4, 2005 Accepted February 22, 2006 Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2 Johannes Jung, Georg Bohn, Anna Allroth, Kaan Boztug, Gudrun Brandes, Inga Sandrock, Alejandro A Schaffer, Chozhavendan Rathinam, Inga Kollner, Carmela Beger, Reinhard Schilke, Karl Welte, Bodo Grimbacher, and Christoph Klein* Division of Rheumatology and Clinical Immunology, Medical Center, Freiburg University Hospital, Freiburg, Germany Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany Department of Cell Biology, Hannover Medical School, Hannover, Germany Department of Health and Human Services, Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, USA Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany Department of Conservative Dentistry and Periodontology, Medical School Hannover, Hannover, Germany * Corresponding author; email: klein.christoph{at}mh-hannover.de. We report on the molecular etiology of an unusual clinical phenotype associating congenital neutropenia, thrombocytopenia, developmental delay, and hypopigmentation. Using genetic linkage analysis and targeted gene sequencing, we defined a homozygous genomic deletion in AP3B1, the gene encoding the chain of the adaptor protein (AP)-3 complex. The mutation leads to in-frame skipping of exon 15 and thus perturbs proper assembly of the heterotetrameric AP-3 complex. Consequently, trafficking of transmembrane lysosomal proteins is aberrant, as shown for CD63. In basal keratinocytes, the incorporated immature melanosomes were rapidly degraded in large phagolysosomes. Despite distinct ultramorphological changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunological assessment revealed that natural killer (NK) and NKT cell numbers were reduced in AP-3-deficient patients. Our findings extend the clinical and molecular phenotype of human AP-3 deficiency (also known as Hermansky-Pudlak syndrome, type 2) and provide further insights into the role of the AP-3 complex for the innate immune system. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. C. Anand, L. Daboussi, T. C. Lorenz, and G. S. Payne Genome-wide Analysis of AP-3-dependent Protein Transport in Yeast Mol. Biol. Cell, March 1, 2009; 20(5): 1592 - 1604. [Abstract] [Full Text] [PDF] G P Spickett Immune deficiency disorders involving neutrophils J. Clin. Pathol., September 1, 2008; 61(9): 1001 - 1005. [Abstract] [Full Text] [PDF] M. Donini, S. Fontana, G. Savoldi, W. Vermi, L. Tassone, F. Gentili, E. Zenaro, D. Ferrari, L. D. Notarangelo, F. Porta, et al. G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms Blood, June 1, 2007; 109(11): 4716 - 4723. [Abstract] [Full Text] [PDF] H. Kikuta, M. Laplante, P. Navratilova, A. Z. Komisarczuk, P. G. Engstrom, D. Fredman, A. Akalin, M. Caccamo, I. Sealy, K. Howe, et al. Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates Genome Res., May 1, 2007; 17(5): 545 - 555. [Abstract] [Full Text] [PDF] M. S. Horwitz, Z. Duan, B. Korkmaz, H.-H. Lee, M. E. Mealiffe, and S. J. Salipante Neutrophil elastase in cyclic and severe congenital neutropenia Blood, March 1, 2007; 109(5): 1817 - 1824. [Abstract] [Full Text] [PDF] K. Newell-Litwa, E. Seong, M. Burmeister, and V. Faundez Neuronal and non-neuronal functions of the AP-3 sorting machinery J. Cell Sci., February 15, 2007; 120(4): 531 - 541. [Abstract] [Full Text] [PDF]

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