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Griscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GS patients. Here, we describe a new patient, possessing a hemophagocytic syndrome with a homozygous Q118X nonsense RAB27A mutation. Single specific primer–polymerase chain reaction (SSP-PCR) was developed based on this mutation and is currently used in prenatal genetic analysis. As expected, CTLs in the patient are not functional and NK cytotoxicity against K562 or 721.221 cells is diminished. Surprisingly, however, we demonstrate that CD16-mediated killing is intact in this patient and is therefore RAB27A independent, whereas NKp30-mediated killing is impaired and is therefore RAB27A dependent. We further analyzed the signaling pathways of these 2 receptors and demonstrated phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. Thus, we identify a novel homozygous mutation in the RAB27A gene of a new GS patient, observe for the first time that some activating NK receptors function in GS patients, and demonstrate a functional dichotomy in the killing mediated by these human NK-activating receptors.

Griscelli syndrome (GS) was diagnosed in a 2-year-old patient with oculocutaneous albinism and immunodeficiency, but sequencing of RAB27a revealed only a heterozygous mutation. Due to impaired natural killer (NK) and T-cell cytotoxicity implying a high risk of developing hemophagocytic lymphohistiocytosis (HLH), he was prepared for hematopoietic stem cell transplantation (HSCT). Unexpectedly, a severe bleeding episode occurred that led to the demonstration of disturbed platelet aggregation, reduced plateletdense granules, and impaired platelet degranulation. In combination with neutropenia, this suggested the diagnosis of Hermansky-Pudlak syndrome type II (HPSII) and a novel homozygous mutation in AP3B1 was detected. None of the 3 reported HPSII patients had developed HLH, and our patient seroconverted to Epstein-Barr virus (EBV) without clinical symptoms. HSCT was therefore withheld, and granulocyte-colony-stimulating factor (G-CSF) therapy was initiated and prevented further bacterial infections. At 3 years of age, however, the patient developed, without an obvious trigger, fulminant HLH that was resistant to therapy. This patient shows that careful clinical and molecular diagnosis is essential to differentiate the complex disorders of lysosomal trafficking. HPSII belongs to the group of familial hemophagocytic syndromes and may represent an indication for HSCT. (Blood. 2006;108:81-87)

To the editor: Partial albinism and primary immunodeficiency occur in several autosomal recessive disorders, including Hermansky-Pudlak syndrome type 2 (HPS2, Online Mendelian Inheritance in Man [MIM] #608233), Chediak-Higashi syndrome (MIM#214500), Griscelli syndrome types 1 (MIM#214450) and 2 (

The ashen (ash) mouse, a model for Hermansky-Pudlak syndrome (HPS) and for a subset of patients with Griscelli syndrome, presents with hypopigmentation, prolonged bleeding times, and platelet storage pool deficiency due to a mutation which abrogates expression of the Rab27a protein. Platelets of mice with the ashen mutation on the C3H/HeSnJ inbred strain background have greatly reduced amounts of dense granule components such as serotonin and adenine nucleotides though near-normal numbers of dense granules as enumerated by the dense granule-specific fluorescent dye mepacrine. Thus, essentially normal numbers of platelet dense granules are produced but the granule interiors are abnormal. Collagen-mediated aggregation of mutant platelets is significantly depressed. No abnormalities in the concentrations or secretory rates of 2 other major platelet granules, lysosomes and alpha granules, were apparent. Similarly, no platelet ultrastructural alterations other than those involving dense granules were detected. Therefore, Rab27a regulates the synthesis and secretion of only one major platelet organelle, the dense granule. There were likewise no mutant effects on levels or secretion of lysosomal enzymes of several other tissues. Together with other recent analyses of the ashen mouse, these results suggest a close relationship between platelet dense granules, melanosomes of melanocytes and secretory lysosomes of cytotoxic T lymphocytes, all mediated by Rab27a. Surprisingly, the effects of the ashen mutation on platelet-dense granule components, platelet aggregation, and bleeding times were highly dependent on genetic background. This suggests that bleeding tendencies may likewise vary among patients with Griscelli syndrome and HPS with Rab27a mutations.

Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disease characterized by defects in trafficking of intracellular vesicles to lysosome-related organelles such as melanosomes, lung lamellar bodies and platelet dense granules. The ashen (rab27a) mouse coat color mutant maintained at Roswell Park Cancer Institute (ash-Roswell) has been proposed as an animal model of HPS based upon prolonged bleeding times, decreased platelet aggregation and greatly decreased platelet dense granule components, including serotonin and ADP. However, human patients with Rab27a deficiency (Griscelli Syndrome) and other isolates of mouse ashen mutants do not exhibit prolonged bleeding suggesting an additional mutation in a gene affecting platelets but not melanocytes in the ash-Roswell mouse. In order to identify this mutation, a backcross between ash-Roswell and the PWK control strain was analyzed. In 390 backcross progeny, deficient platelet serotonin and diluted coat color (Rab27a) phenotypes segregated independently and in the proportions expected for single gene traits. The gene for serotonin deficiency was narrowed to a 2.1Mb region of mouse chromosome 10 containing 15 genes. None of these genes have been implicated previously in platelet storage pool deficiency. These studies indicate this genomic region contains a gene which uniquely controls platelet dense granules and is a candidate gene for a new form of human HPS.