Disorders of Vesicles of Lysosomal Lineage: The Hermansky- Pudlak Syndromes

Huizing, Marjan; Gahl, William A.

doi:10.2174/1566524023362357

Cited by 108 publications

(82 citation statements)

References 82 publications

(161 reference statements)

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“…20 It is ubiquitously expressed and functions to recruit cargo proteins to the newly formed vesicles and transport them to late endocytic compartments. 21,22 Defects in the ␤3A subunit disrupt the complex and all subunits are rapidly degraded.…”

Section: Discussionmentioning

confidence: 99%

Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II

Enders

Zieger

Schwarz

et al. 2006

Blood

194

143

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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 ly- IntroductionSecretory lysosomes are cellular organelles involved in trafficking and exocytosis of intracellular proteins. 1 They have important functions in several cell types including melanocytes, neuronal cells, platelets, granulocytes, mast cells, natural killer (NK) cells, and T cells. 2 The protein machinery required for adequate biogenesis, transport, and delivery of secretory lysosomes has a variable composition in each cell type. Therefore, the clinical phenotype of diseases due to genetic defects in proteins involved in lysosomal trafficking varies widely despite the similar cell-biologic basis. This has led to their classification as predominantly dermatologic, hematologic, hemostaseologic, or immunologic disorders. While the 7 genetically defined Hermansky-Pudlak syndromes (HPSs) predominantly present as bleeding disorders, 3 the most important clinical problem of patients with Chédiak-Higashi syndrome (CHS) and Griscelli syndrome type II (GSII) is immunodeficiency. 4 Neurologic defects characterize GSI and CHS, 5 while patients with GSIII show only oculocutaneous albinism. 6 This latter feature links all of these syndromes. However, studies showing that also some forms of familial hemophagocytic lymphohistiocytosis (FHL) represent lysosomal trafficking disorders 7,8 revealed that albinism is not a constant feature in this heterogenous family of diseases.Lysosomal trafficking disorders associated with immunodeficiency are life-threatening conditions due to the high risk of developing hemophagocytic lymphohistiocytosis (HLH). 4 HLH is a systemic inflammatory disorder characterized by uncontrolled CD8 ϩ T-cell and macrophage activation with infiltration of multiple tissues. 9 The common defect in most genetic diseases predisposing to HLH is disturbed secretion of ...

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Section: Discussionmentioning

confidence: 99%

Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II

Enders

Zieger

Schwarz

et al. 2006

Blood

194

143

View full text Add to dashboard Cite

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“…A lysosome-related organelle invariably affected in all HPS patients and animal models is the platelet dense granule (5,7,8). Typically, platelet dense granules are either missing or greatly reduced in number.…”

Section: In Vivo Physiological Interactions Of Hps3 Hps5 and Hps6 Pmentioning

confidence: 99%

“…Organellar trafficking abnormalities lead, in turn, to hypopigmentation of both coat and eyes and prolonged bleeding times. All three mutants are appropriate animal models for the inherited human disease Hermansky-Pudlak syndrome (HPS) 1 (Mendelian Inheritance in Man, 203300) (7,8), which presents with similar abnormalities of subcellular organelles. Associated clinical symptoms of HPS include loss of visual acuity, prolonged bleeding, and lung disease due to abnormalities of melanosomes, platelet dense granules, and lysosomes, respectively.…”

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confidence: 99%

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The Hermansky-Pudlak Syndrome 3 (Cocoa) Protein Is a Component of the Biogenesis of Lysosome-related Organelles Complex-2 (BLOC-2)

Gautam

Chintala

et al. 2004

Journal of Biological Chemistry

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Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous inherited disease affecting vesicle trafficking among lysosome-related organelles. The Hps3, Hps5, and Hps6 genes are mutated in the cocoa, rubyeye-2, and ruby-eye mouse pigment mutants, respectively, and their human orthologs are mutated in HPS3, HPS5, and HPS6 patients. These three genes encode novel proteins of unknown function. The phenotypes of Hps5/Hps5,Hps6/Hps6 and Hps3/Hps3,Hps6/Hps6 double mutant mice mimic, in coat and eye colors, in melanosome ultrastructure, and in levels of platelet dense granule serotonin, the corresponding phenotypes of single mutants. These facts suggest that the proteins encoded by these genes act within the same pathway or protein complex in vivo to regulate vesicle trafficking. Further, the Hps5 protein is destabilized within tissues of Hps3 and Hps6 mutants, as is the Hps6 protein within tissues of Hps3 and Hps5 mutants. Also, proteins encoded by these genes co-immunoprecipitate and occur in a complex of 350 kDa as determined by sucrose gradient and gel filtration analyses. Together, these results indicate that the Hps3, Hps5, and Hps6 proteins regulate vesicle trafficking to lysosome-related organelles at the physiological level as components of the BLOC-2 (biogenesis of lysosome-related organelles complex-2) protein complex and suggest that the pathogenesis and future therapies of HPS3, HPS5, and HPS6 patients are likely to be similar. Interaction of the Hps5 and Hps6 proteins within BLOC-2 is abolished by the three-amino acid deletion in the Hps6 ru mutant allele, indicating that these three amino acids are important for normal BLOC-2 complex formation.

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“…9,10 The pathophysiological basis of these partly overlapping syndromes is a disturbed biogenesis and transport of secretory lysosomerelated organelles. 11,12 These secretory organelles are found in several cell types for secretion of specific, cell-type-dependent proteins and peptides. They are important for diverse physiological processes, including pigmentation of eyes, hair, and skin 13 ; release of small molecules by d granules from platelets at the site of blood vessel damage that facilitate platelet adhesion and activation 7 ; secretion of perforin and granzyme by lytic granules in cytotoxic lymphocytes 11,14 ; and secretion of surfactant by lysosome-related lamellar bodies in pulmonary alveolar type II cells.…”

Section: Introductionmentioning

confidence: 99%