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The Hermansky–Pudlak syndrome (HPS) is a collection of related autosomal recessive disorders which are genetically heterogeneous. There are eight human HPS subtypes, characterized by oculocutaneous albinism and platelet storage disease; prolonged bleeding, congenital neutropenia, pulmonary fibrosis, and granulomatous colitis can also occur. HPS is caused primarily by defects in intracellular protein trafficking that result in the dysfunction of intracellular organelles known as lysosome-related organelles. HPS gene products are all ubiquitously expressed and all associate in various multi-protein complexes, yet HPS has cell type-specific disease expression. Impairment of specialized secretory cells such as melanocytes, platelets, lung alveolar type II epithelial cells and cytotoxic T cells are observed in HPS. This review summarizes recent molecular, biochemical and cell biological analyses together with clinical studies that have led to the correlation of molecular pathology with clinical manifestations and led to insights into such diverse disease processes such as albinism, fibrosis, hemorrhage, and congenital neutropenia.
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In 1959, the Czechoslovakian physicians Hermansky and Pudlak described two patients with oculocutaneous albinism, prolonged bleeding and pigmented macrophages in the bone marrow; one patient also had interstitial pulmonary fibrosis and died at 34 yr of age (Hermansky and Pudlak, 1959). Since that time, the Hermansky–Pudlak syndrome (HPS), has been recognized as a genetically heterogeneous set of related autosomal recessive conditions due to mutations in genes that mostly function in membrane and protein trafficking. Defects in proteins encoded by these genes can affect the biogenesis and/or function of intracellular organelles found in specialized secretory cells such as pigment cells (i.e. melanocytes and pigment epithelial cells), platelets, T cells, neutrophils, and lung type II epithelial cells. The organelles affected by HPS genes belong to the family of organelles known as lysosome-related organelles (LROs), which share in common with lysosomes at least one integral membrane protein and intralumenal acidic pH (Cutler, 2002; Dell'Angelica et al., 2000b). Although HPS disease phenotype appears to be confined to only certain specialized cell types, expression of HPS genes has been detected in all tissues tested, and HPS genes are thought to be ubiquitously expressed.
There are eight known human HPS genes, each of which can lead to a particular clinical HPS subtype. There are 15 murine HPS genes, which have been cloned and sequenced; eight of the mouse genes are orthologous to the eight human HPS genes (Table 1), and many HPS genes have orthologues in the Drosophila melanogaster genome as well (Dell'Angelica, 2004). It is likely that additional human HPS subtypes will be described, corresponding to the known mouse strains.
Table 1. Hermansky–Pudlak syndrome subtypes and corresponding mouse strains
|Human subtype||Mouse strain||Gene||Function|
|HPS-2||Pearl||AP3B1||Cargo selection and vesicle trafficking to the lysosome|
|HPS-7||Sandy||DTNBP1||Binds α- and β-dystrobrevin, myospryn|
|?||Pallid||Pldn||Binds syntaxin 13|
|?||Buff||VPS33A||Vesicle trafficking to yeast vacuole|
|?||Gunmetal||RABGGTA||Adds lipophilic prenyl groups to carboxyl terminus of rab proteins|
|?||Mocha||AP3D1||Cargo selection & vesicle trafficking to the lysosome|
|?||Subtle gray||Slc7a11||Cystine/glutamate exchanger xCT|
Of the 15 identified HPS genes, only five have known functions (AP3B1, AP3D1, VPS33A, RABGGTA, and Slc7a11), and four of these have roles in regulating membrane/vesicle and protein trafficking. The AP3B1 gene encodes the β subunit and AP3D1 encodes the δ subunit of the adaptor protein AP-3, which plays a role in enriching cargo proteins in vesicles for transport through the intracellular endosomal/lysosomal pathway. The VPS33A gene encodes a protein that is part of the class C Vps complex (C-Vps complex) which plays an integral role in vesicular trafficking to the yeast vacuole, an organelle functionally homologous to the mammalian lysosome (Suzuki et al., 2003), by binding a syntaxin homolog to mediate transport vesicle docking and fusion with a target membrane such as the vacuolar membrane (Sato et al., 2000; Suzuki et al., 2003). The C-Vps complex is also a component of the larger HOPS complex which is essential for vacuole to vacuole fusion and vacuole protein sorting (Seals et al., 2000). The RABGGTA gene product Rab geranylgeranyl transferase-α is a subunit of a heterodimer that attaches prenyl moieties to Rab molecules, which are small GTP-binding proteins in the Ras-like GTPase superfamily which regulate vesicular trafficking and organelle motility (Detter et al., 2000).
Two other HPS gene products are known to bind to previously described proteins. The dystrobrevin binding protein-1 (DTNBP1) gene product is dysbindin, that binds to α- and β-dystrobrevins, components of the dystrophin-associated protein complex (Benson et al., 2001), which is found at the synapses in brain and muscle cells (Sillitoe et al., 2003); dysbindin has been suggested to play a role in the exocytosis of glutamate in neuronal cells (Numakawa et al., 2004). The Pldn gene product, pallidin, binds to syntaxin 13 in yeast two hybrid studies (Huang et al., 1999). Syntaxin 13 is a member of the SNARE family of molecules that mediate membrane docking and fusion (Advani et al., 1998); the interaction of syntaxin 13 with pallidin suggests a role for pallidin in membrane trafficking.
The only HPS gene of known function that does not have an identified role in protein or membrane trafficking, Slc7a11, is defective in the subtle gray mouse strain, which has been classified as a model for mild HPS because of mild depression of platelet dense granule numbers by electron microscopic examination (Swank et al., 1996). Slc7a11 encodes the cystine/gutamate exchanger xCT (Chintala et al., 2005). This protein appears to regulate the ratio of pheomelanin and melanin synthesized in melanocytes, and affects cells’ ability to respond to oxidative stress.
Strikingly, many of the HPS proteins have one or two predicted regions of coiled coil motif, which have been implicated in protein–protein interactions (Burkhard et al., 2001; Dell'Angelica, 2004). Furthermore, all of the HPS proteins are associated in multi-protein complexes, the majority involving multiple HPS proteins (Table 2). Thus, biogenesis of lysosome-related organelle complex-1 (BLOC-1) includes as subunits the HPS proteins pallidin, cappuccino, muted, reduced pigmentation (rp) and dysbindin (Ciciotte et al., 2003; Falcon-Perez et al., 2002; Gwynn et al., 2004; Starcevic and Dell'Angelica, 2004); BLOC-2 has as subunits the HPS3, HPS5, and HPS6 proteins (Di Pietro et al., 2004; Gautam et al., 2004; Zhang et al., 2003); BLOC-3 contains HPS1 and HPS4 proteins (Chiang et al., 2003; Martina et al., 2003; Nazarian et al., 2003). The adapter protein complex AP-3 includes the β3A subunit, defective in HPS-2 (Dell'Angelica et al., 1999) and the δ-subunit, defective in the murine HPS mocha strain (Kantheti et al., 1998). Two other proteins, VPS33A and RGGTA, are defective in murine HPS, and are also known to form multiprotein complexes (Detter et al., 2000; Rieder and Emr, 1997; Seals et al., 2000) but no human diseases have yet been found to be caused by defects in these proteins.
Table 2. Hermansky–Pudlak syndrome protein complexes
|AP-3||β3A δ μ3 σ3|
|BLOC-1||Pallidin Cappuccino Muted Reduced pigmentation/BLOS3a Dysbindin Snapin BLOS1 BLOS2|
|BLOC-2||HPS3 HPS5 HPS6|
|Predicted complex||Predicted subunits|
|VpsC complex||Vps33a, Vps11, Vps16, Vps18|
|Rab geranylgeranyl transferase||Rabggta, Rabggtb|
Clinically, HPS is defined by pigment dilution (affecting skin, hair, and eyes) – resulting in oculocutaneous albinism – and platelet storage pool deficiency (causing prolonged bleeding), but different HPS subtypes have additional distinguishing features, discussed in subsequent sections. Some subtypes, notably HPS-1 and HPS-4, can be debilitating and can lead to premature mortality; there is no known cure or effective therapy for HPS. A diagnosis of HPS can be made by (1) an ophthalmologic examination showing iris transillumination, fundus hypopigmentation, the presence of nystagmus and decreased visual acuity; and (2) a wet mount electron microscopic examination of platelets showing absent or greatly decreased numbers of platelet dense granules (organelles that store ATP, ADP, calcium, serotonin for release upon platelet aggregation) (Huizing and Gahl, 2002). Accumulation of an autofluorescent ceroid-like material can be detected in the reticuloendothelial system (Nakatani et al., 2000; White et al., 1973; Witkop et al., 1989). Confirmation of the diagnosis and subtyping is done by molecular analysis demonstrating mutation of an HPS gene.
Even in cases in which mutations in HPS genes are identified, ascertaining and attributing gene effects can sometimes be tentative due to low numbers of patients (in some HPS subtypes only one to three patients have been identified) and background gene effects (i.e. mutations or polymorphisms in other genes) can be difficult to control for. Studying the mouse models of HPS can be illuminating, as most of the HPS subtypes occurred spontaneously in or were bred subsequently onto a common inbred genetic background (C57BL/6), and gene effects can be more reliably identified. However, the mouse strains do not harbor the same mutations as seen in human patients, so phenotypes occurring in humans may not be represented in the mouse strains. The study of both HPS affected patients and mice has yielded complementary information that has recently allowed a better understanding of the pathogenesis and cellular basis of HPS, and has spurred interest in HPS in diverse fields such as dermatology, ophthalmology, pulmonology, hematology, genetics and cell biology.
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Hermansky–Pudlak syndrome is an example of a genetically heterogeneous syndrome that is the result of defects in protein trafficking along the endocytic/lysosomal pathway. HPS gene products can be divided into two types. Group A (AP3B1, AP3D1, RABGGTA, and VPS33A), are those that have homologues in yeast, which regulate trafficking to the yeast vacuole and in higher eukaryotes function as major regulators of trafficking to the lysosome. In contrast, the remaining HPS group B gene products (HPS1, HPS3, HPS4, HPS5, HPS6, DTNBP1, HPS8, Pldn, cno, and mu), are only found in metazoans (Li et al., 2004), and although containing regions with some homology to yeast proteins (Hoffman-Sommer et al., 2005), they have apparently developed as specialized cell types evolved with the need to form specialized organelles. This evolutionary development, together with the preponderance of data accumulating on the cellular effects of defects in HPS proteins, suggests that the HPS group B proteins function primarily to regulate membrane and protein trafficking to the ‘newer’ specialized organelles, the LROs, but may also contribute to lysosomal trafficking.
Mechanisms for cell type-specific disease expression
One intriguing aspect of HPS has been that the disease expression seems to be limited to a certain few specialized cell types despite ubiquitous tissue expression of HPS proteins. One explanation could lie in the way that different cell types developed pathways of biogenesis for their specialized organelles. In some specialized cell types, such as the cytotoxic T cells (CTL), the specialized organelle (in this case the lytic granule), is a secretory lysosome; i.e. there are no separate lysosomes distinct from the lytic granule (Stinchcombe and Griffiths, 1999). In contrast, in another specialized cell type, the melanocyte, studies suggested that the specialized organelle (the melanosome) coexists in the cell with lysosomes (Raposo et al., 2001). This may have implications regarding the impact of defects in HPS group A vs. group B proteins. Group B proteins might not affect cells with secretory lysosomes but rather primarily affect cells which had specialized LRO organelles that were distinct from lysosomes. Consistent with this prediction is the finding that the function of CTLs deficient in BLOC-1, -2, and -3 was found to be normal (Bossi et al., 2005).
Another potential mechanism for cell type specificity is illustrated in the case of the protein affected in HPS-7, dysbindin, which is observed to have a tissue specific protein binding partner, myospryn. So while the HPS proteins are ubiquitous, it is likely that HPS proteins function via binding to cell-type specific effectors (e.g. myospryn) and/or tissue-specific cargo such as tyrosinase (found only in pigment cells). Similarly, in the case of AP-3, the defective complex in HPS-2, tissue specific neuronal subunits provide a mechanism for mediating brain specific functions such as synaptic vesicle biogenesis. An additional mechanism contributing to cell-type specificity may come from regulating differential expression levels of HPS proteins in different cells types. For example, a particular antibody was able to detect endogenous HPS1 protein in human melanoma cells by immunoblotting and immunoprecititation, but was unable to detect endogenous HPS1 protein in HeLa cells by the same methods (Dell'Angelica et al., 2000a; Sarangarajan et al., 2001), suggesting the possibility that pigment cells may express higher levels of HPS1 compared with non-pigment cells. Further tissue specific regulation may derive from cell type-specific use of alternative transcripts; for example, alternatively spliced isoforms of HPS5 and HPS4 are expressed at different levels in different tissues (Anderson et al., 2003; Huizing et al., 2004).
Molecular pathology and HPS clinical subtypes
While all HPS patients suffer from oculocutaneous albinism (OCA) and prolonged bleeding, different subtypes, some with distinguishing features, are now recognized. Recent genetic and biochemical characterizations of HPS subtypes have enabled the classification of the subtypes into groups (Table 3); the heterogeneous clinical phenotypes of HPS can now be understood in the context of the molecular pathology. HPS-1 and HPS-4 subtypes are similar in causing the most serious morbidity and premature mortality, with affected individuals at high risk for developing restrictive pulmonary disease and inflammatory bowel disease. These clinical similarities reflect the molecular association of HPS1 and HPS4 to form the intracellular BLOC-3 complex; this complex regulates the biogenesis and/or function of the lung lamellar body as well as the platelet dense body and the melanosome. HPS-2 is unique in causing immunodeficiency. The HPS-3, HPS-5, and HPS-6 subtypes are clinically similar; the respective proteins associate to form the BLOC-2 complex, and defects in these proteins result in relatively mild symptoms of platelet dysfunction, without pulmonary involvement. Patients with HPS-7 and HPS-8, due to defects in BLOC-1 subunits, had moderate signs and symptoms of HPS: OCA, a bleeding tendency and mild pulmonary symptoms (in the case of HPS-7). The relatively mild systemic symptoms of HPS-7 and HPSS-8 contrast with the markedly severe pigmentary phenotype observed in the mouse strains deficient in BLOC-1 genes; however, the moderate phenotype of the few reported patients affected by defects in BLOC-1 may not be representative of BLOC-1 patients in general.
Table 3. Clinical manifestations of HPS subtypes
|HPS subtype||Protein complex||Clinical manifestations|
The pigment dilution in HPS appears to result from mistrafficking of melanogenic enzymes such as tyrosinase, which leads to decreased melanin production. The trafficking of additional other melanocyte factors may also be affected, as melanosome biogenesis appears to be blocked at immature stages. The bleeding diatheses appear to be secondary to mistrafficking of the MRP4/ABCC4 transporter in platelets with a consequent lack of intralumenal vesicular loading of nucleotides, leading to decreased secretion of these nucleotides with platelet aggregation and impaired clotting. Pulmonary fibrosis appears to result from impaired secretion of surfactant and phospholipids from abnormal appearing lung lamellar bodies. Moreover, congenital neutropenia results from mistrafficking of NE. Thus, defects in protein trafficking pathways and organelle function account for much of the pathophysiology seen in HPS (Table 4).
Table 4. HPS: disease of protein trafficking to lysosome related organelles
|Organelle||Cell type||Mistrafficked protein(s)||HPS subtype|
|Tyrp1, DCT/TRP2, CD63||HPS-1, HPS-3|
|Dense granule||Platelet||MRP4/ABCC4, CD63||HPS-4|
|Lytic granule||Cytotoxic T cell||CD63||HPS-2|
|Azurophilic granule||Neutrophil||Neutrophil elastase||HPS-2|
|Lamellar body||Lung type II epithelial cell||?||HPS-1, HPS-4|
HPS and melanocyte protein trafficking
Studies of HPS have also added to the understanding of critical aspects of melanocytes function. In humans and mice, the two major forms of pigment synthesized by melanocytes are eumelanin, or black/brown melanin, stored in eumelanogenic melanosomes, and pheomelanin, or yellow/red melanin, stored in pheomelanogenic melanosomes. Past study of the biogenesis of melanosomes was facilitated by the observation of four morphologically distinct stages of eumelanogenic melanosome development (Marks and Seabra, 2001; Seiji et al., 1963). Recent morphological studies were done which analyzed where melanosome biogenesis was blocked in melanocytes derived from HPS mice (Nguyen and Wei, 2004; Nguyen et al., 2002) and suggested an ordering for HPS protein function along the pathway of melanosome biogenesis (Figure 8).
Figure 8. HPS protein complexes function along the pathway of melanosome biogenesis. Mutations in genes encoding BLOC-1 components cause accumulation of stage I melanosomes and numerous aberrant vesicular structures lacking intralumenal striations, whereas defects in BLOC-2 components cause accumulation of stage I melanosomes and a novel melanosome intermediate, stage Ia, which is similar to stage I melanosomes in being vacuolar and not elliptical, but which contains intraluminal striations. BLOC-3 appears to function early in melanosome biogenesis as well, causing accumulation of stage I melanosomes. In mouse dorsal back follicular melanocytes, defects in BLOC-3 components introduce a mild rate limiting step and accumulation of stage I melanosomes (Nguyen et al., 2002), but in tail epidermal melanocytes, a more pronounced block in melanosome biogenesis is observed, so that mature melanosomes were relatively decreased in number (M.L. Wei and T. Nguyen, personal communication), suggesting that HPS proteins may differentially regulate melanocytes located in separate anatomic niches. Defects in the δ-subunit of AP-3 affect melanosome maturation between stage III and IV. Mutation of the Rabggta subunit of Rab geranylgeranyl transferase prevents the association of melanosomes with cortical actin filaments and impedes secretion of melanin particles into the extracellular space. BLOS3 is also known as HPS8/reduced pigmentation.
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A model depicting trafficking pathways in the melanocyte, incorporating the data from HPS cells, together with recent studies on melanosome biogenesis and protein trafficking to the melanosome, is shown in Figure 9. At the trans-Golgi network (TGN), newly synthesized molecules destined ultimately for the lysosome or the melanosome are likely to undergo a first round of sorting. Molecules such as Pmel17 (a melanocyte-specific protein targeted to melanosomes and an integral component of the intra-lumenal fibrils) and MART-1/melan-a (a melanocyte-specific protein of unknown function) appear to be transported to the stage I melanosome, possibly via an AP1 mediated mechanism (De Maziere et al., 2002; Raposo et al., 2001). The syntaxin 13 molecule is localized to stage I melanosomes/coated endosomes (De Maziere et al., 2002; Prekeris et al., 1998), and the BLOC-1 subunit pallidin binds syntaxin 13 in yeast two-hybrid studies (Huang et al., 1999), suggesting a role for BLOC-1 at the level of the stage I melanosome, perhaps in mediating fusion events, as syntaxin 13 plays a role in endosomal fusion (Prekeris et al., 1998). Moreover, supporting a function for BLOC-1 at this early step in melanosome biogenesis are melanosome morphologies in the majority of BLOC-1 defective mice (pallid, cappuccino, muted, and sandy) that exhibited a block in melanosome maturation at the level of the stage I melanosome (Nguyen and Wei, 2004; Nguyen et al., 2002).
Figure 9. Model of trafficking pathways in melanocytes mediated by HPS proteins. Melanosomal proteins such as MART-1 and Pmel17 exit the TGN and traffic to the stage I melanosome/coated endosome via AP-1. Targeting and fusion of transport vesicles is possibly mediated by BLOC-1 binding to syntaxin 13. LAMP-1 and tyrosinase are transported to an early endosome via AP-1, then tyrosinase proceeds to later stage melanosomes via AP-3 and BLOC-3, whereas LAMP-1 continues on to late endosomes and lysosomes. BLOC-2 may mediate transport vesicle targeting, docking or fusion to later stage melanosomes and lysosomes. Tyrp1 is transported directly from the TGN to later stage melanosomes via BLOC-3 function. Alternatively, both tyrosinase and Tyrp1 could traffic to the late endosome via AP-3 and AP-1, respectively, and then traffic via BLOC-3 to the melanosome. After secretion of melanin, via fusion of the melanosomal limiting membrane with the plasma membrane, integral membrane molecules spanning the melanosome limiting membrane would remain on the cell surface, and are predicted to be internalized into endosomes and subsequently trafficked to lysosomes for degradation. Consistent with this are data which demonstrated MART-1, Pmel17 and Tyrp1 on the cell surface and also colocalizing with the lysosomal marker LAMP-1 (De Maziere et al., 2002; Levy et al., 2005; Raposo and Marks, 2002; Sprong et al., 2001). TGN, trans-Golgi network; MVB, multivesicular body.
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Other molecules such as Tyrp1 and tyrosinase are likely targeted to later stage II or III melanosomes (Kushimoto et al., 2001; Raposo et al., 2001), but may arrive via distinct routes. Steady state distribution of tyrosinase was disrupted in AP-3-deficient melanocytes (Huizing et al., 2001b), but Tyrp1 was unaffected, suggesting that trafficking of tyrosinase is AP3-dependent and that of Tyrp1 is not. Tyrosinase appears to be targeted to melanosomes via an endosomal route, and seems to follow an initial pathway similar to that taken by the LAMP-1 and -3 molecules. In AP-3 deficient melanocytes, tyrosinase accumulated in multivesicular structures with tubular extensions resembling early endosomes (Huizing et al., 2001b) and in AP-3 deficient CTL, LAMP-3/CD63 also appeared to accumulate in endosomal structures, colocalizing with the early endosomal marker EEA1 (Clark et al., 2003). Studies on mouse fibroblasts deficient in AP-3 and AP-1 molecules have suggested that AP-1 mediates trafficking from Golgi to endosome and that AP-3 mediates trafficking from endosomes to lysosomes (Reusch et al., 2002). The data for melanocytes seems to be consistent with the findings in fibroblasts, with the extension that AP-3 mediates trafficking to melanosomes as well, as tyrosinase is mis-localized in the absence of AP-3 (Huizing et al., 2001b).
Genetic and morphological data in mice indicated that BLOC-1 mediated events likely precede BLOC-3 mediated events, and that BLOC-1 and BLOC-3 may work sequentially along the same pathway, as doubly homozygous pa/pa, ep/ep mice had the same pigmentary phenotype as BLOC-1 pallid mice (Nazarian et al., 2003). Immunoelectron microscopy studies co-localized Tyrp1 and AP-1 in the vicinity of the TGN and suggested that Tyrp1 may exit the TGN via an AP-1-mediated route and traffic directly to stage II melanosomes, persisting in stage III and IV melanosomes (Raposo et al., 2001). In cultured melanocytes derived from HPS-1 patients, defective in BLOC-3, Tyrp1 is found in large vesicles as well as in granular structures, compared with in control cells in which only the granular structures are noted (Richmond et al., 2005). Together, the data are consistent with Tyrp1 trafficking to early melanosomes from the TGN via an AP-1 and BLOC-3-dependent pathway. In the absence of HPS1, Tyrp1 may be arrested in the TGN or mislocalized to endosomal/lysosomal structures. The localization of HPS1 near the Golgi and on uncoated vesicles and on early melanosomes (Oh et al., 2000) suggests that HPS1 may play a role in the transport of vesicles destined for the melanosome. Ultrastructural analysis of melanosome morphology in mice defective in BLOC-3 is consistent with a role for BLOC-3 in melanosome biogenesis before the stage II melanosome, but after the delivery of Pmel17 to premelanosomes (Nguyen et al., 2002). In cells from HPS-1 patients, tyrosinase is also found in large vesicles, similarly to the effect on Tyrp1 (Richmond et al., 2005), again consistent with BLOC-3 having a role in vesicular transport to the melanosome.
In mice, the BLOC-2 subunit Hps6 is suggested to mediate fusion of transport vesicles to the plasma membrane (Oberhauser and Fernandez, 1996), and may likewise mediate fusion events at the level of the melanosome (and lysosome). In the absence of the BLOC-2 subunit HPS3, melanocytes from patients exhibited a more diffuse cytoplasmic distribution of tyrosinase, Tyrp1, LAMP-1, and LAMP-3, compared with a granular distribution in control cells (Richmond et al., 2005) and ultrastructural studies demonstrated an increased abundance of 50 nm vesicles containing pigment in the presence of dihydroxy-phenylalanine (DOPA), suggesting the intraluminal presence of either tyrosinase or Tyrp1 enzymatic activity (Boissy et al., 2005). The steady state distribution of Pmel17 and MART-1 were normal (Boissy et al., 2005). Thus BLOC-2 may mediate the fusion of transport vesicles containing tyrosinase or Tyrp1 with stage II or III melanosomes and vesicles containing LAMP-1 and LAMP-3 with melanosomes and/or lysosomes.
HPS effects on LROs
How have HPS defects affected other LROs, such as platelet dense bodies, lytic granules, and lung lamellar bodies? A common theme appears to be defects in secretion of many of these organelles. Skin cells from light ear mice (defective in HPS4) have decreased basal secretion of lysosomal hydrolases (Delprato et al., 2000). Platelets have abnormal thrombin stimulated secretion of dense granule contents (Novak et al., 1984). Lamellar bodies in lung alveolar type II epithelial cells in pale ear/pearl double homozygous mice (defective in HPS1 and AP-3 proteins) have decreased basal and ATP-stimulated secretory capacity for surfactant protein and phospholipids (Guttentag et al., 2005). A possible mechanism for the loss in secretory activity is suggested in HPS-1 and HPS-2, in which defective microtubule-meditated organelle motility is demonstrated for lysosomes in fibroblasts (Nazarian et al., 2003) and lytic granules in T cells (Clark et al., 2003), respectively. It could be that one or more motility factors, mediating attachment to or movement along microtubules, are missing or decreased in amount from the affected organelles in HPS, due to mis-targeting. Alternatively, selected HPS proteins may bind to these factors, which may be degraded in the absence of the HPS binding partner. Another possibility for lamellar bodies is that the process of exocytosis rather than motility is defective, and factors mediating events such as vesicle docking, targeting or fusion at the plasma membrane may be missing.
In the case of melanosomes, defects in Rabggta caused a marked block in secretion of melanin and an accumulation of intracellular melanosomes (Nguyen et al., 2002). However, in other HPS mouse strains an accumulation of melanosomes within melanocytes was not observed, and immature melanosomes were noted within neighboring keratinocytes, indicating that aberrant melanosomes were secreted to some extent (Nguyen and Wei, 2004).
In conclusion, the Hermanky–Pudlak syndrome is made up of a complex set of related autosomal recessive disorders caused by underlying defects in protein trafficking. Recent molecular, biochemical and cell biologic analyses together with clinical studies have provided insights into links between molecular and cellular pathology and clinical disease expression. Studies on HPS have led to a deeper understanding of basic cell processes, in particular mechanisms of cell-type specific specialized processes, led to the development of molecular tools to identify increasing numbers of HPS patients, and will likely help lead to targeted therapies for this currently untreatable and often fatal disease.