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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.
PHAGOCYTES Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2From the Division of Rheumatology and Clinical Immunology, Medical Center, Freiburg University Hospital, Germany; the Department of Pediatric Hematology/Oncology, Hannover Medical School, Germany; the Department of Cell Biology, Hannover Medical School, Germany; the Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; the Institute of Cell and Molecular Pathology, Hannover Medical School, Germany; and the Department of Conservative Dentistry and Periodontology, Hannover Medical School, Germany.
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
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
chain of the adaptor protein-3 (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 ultramorphologic changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunologic 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. (Blood. 2006;108:362-369) 
