Hermansky–Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis


  • Ai-Hua Wei,

    1. Department of Dermatology, Beijing Tongren Affiliated Hospital of Capital Medical University, Beijing, China
    2. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing, China
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  • Wei Li

    Corresponding author
    1. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing, China
    • Department of Dermatology, Beijing Tongren Affiliated Hospital of Capital Medical University, Beijing, China
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CORRESPONDENCE W. Li, e-mail: wli@genetics.ac.cn; A.-H. Wei, email: weiaihua3000@163.com


Hermansky–Pudlak syndrome (HPS) is an autosomal recessive and genetically heterogeneous disorder characterized by oculocutaneous albinism, bleeding tendency, and ceroid deposition, which likely leads to deleterious lesions in lungs, heart, and other organs. Currently, nine genes have been identified as causative for HPS in humans. Their pathological effects are attributable to the disrupted biogenesis of lysosome-related organelles (LROs) existing in multiple cell types or tissues, causing the pigmentory and non-pigmentory defects. This review focuses on the functional aspects of HPS genes in regulating LRO biogenesis and signal transduction. The understanding of these mechanisms expands our knowledge about the involvement of lysosomal trafficking in the targeting of cargoes for constitutive transport, degradation, and secretion. This opens an avenue to the pathogenesis of lysosomal trafficking disorders at the cellular and developmental levels.

Introduction to Hermansky–Pudlak syndrome

Clinical features and overview of Hermansky–Pudlak syndrome

Hermansky–Pudlak syndrome (HPS, OMIM 203300; Hermansky and Pudlak, 1959) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and ceroid deposition, which may cause lung fibrosis, colitis, and cardiomyopathy in some cases. Patients with HPS often die during the third to fifth decade (Huizing and Gahl, 2002; Huizing et al., 2000). The key pathological aspect of both human and mouse HPS is the disrupted biogenesis and/or function of lysosome-related organelles (LROs), including melanosomes and platelet-dense granules (DG) as well as secretory lysosomes (Dell'Angelica et al., 2000; Huizing et al., 2008; Li et al., 2004; Swank et al., 1998; Wei, 2006).


Hermansky–Pudlak syndrome is now known as a genetically heterogeneous, autosomal recessive inherited disorder. Nine genes (HPS1, AP3B1, and HPS3 to HPS9) have been identified as causative genes for HPS in humans (Anikster et al., 2001; Cullinane et al., 2011a; Dell'Angelica et al., 1999; Li et al., 2003; Morgan et al., 2006; Oh et al., 1996; Suzuki et al., 2002; Zhang et al., 2003). Additional six genes (Ap3d, Rabggta, Vps33a, Cno, Muted, Kxd1) cause mouse HPS (Li et al., 2004; Yang et al., 2012) and are listed in the HPS database (HPSD, http://liweilab.genetics.ac.cn/HPSD/; Li et al., 2006). As the HPS proteins have been categorized into several lysosomal-trafficking protein complexes such as AP-3, HOPS, BLOC-1, BLOC-2, and BLOC-3 (Di Pietro and Dell'Angelica, 2005; Li et al., 2004), genes encoding the subunits of these complexes that have not been defined as HPS proteins are putative HPS genes, as evidenced by the discovery of the HPS9 gene (Cullinane et al., 2011a).


Hermansky–Pudlak syndrome occurs in many countries, with more than 800 patients reported worldwide. It is almost certainly underestimated because of mis-diagnosis or un-diagnosis. The highest prevalence region of HPS is in Puerto Rico with founder effects. The incidence rate is estimated as 1:1800 with a carrier rate of 1:21 in Puerto Rico (Oh et al., 1996). HPS-1 and HPS-3 are the two common types of HPS in this region (Anikster et al., 2001). Non-Puerto Rican patients with HPS are scattered in many populations as listed in the HPSD database. HPS-1 is the relatively common subtype in Japanese (Ito et al., 2005) and Chinese OCA patients (Wei et al., 2010, 2011).


The pathogenesis underlying HPS results from defects in the biogenesis of LROs, which are described in more detail later.

Clinical manifestation

Symptoms of HPS in humans have been reviewed extensively (DePinho and Kaplan, 1985; Huizing et al., 2008; Spritz, 2000). In 1959, two Czechoslovakian physicians Hermansky and Pudlak first described the pigmentary and non-pigmentary abnormalities in HPS (Hermansky and Pudlak, 1959). The most common symptoms of HPS are hypopigmentation, loss of visual acuity, prolonged bleeding, colitis, and, in some cases, fatal lung disease. Hemophagocytic lymphohistocytosis (Enders et al., 2006) and immune deficiency (Huizing et al., 2002) have been reported in patients with HPS-2. Neuronal symptoms are described in Ap3b1-deficient and Ap3b2-deficient mice (Seong et al., 2005). Participation of mouse AP-3 and BLOC-1 in synaptic vesicle biogenesis implicates potential neuronal dysfunction in patients with HPS (Chen et al., 2008; Larimore et al., 2011; Newell-Litwa et al., 2010). Although the dysbindin-null sdy mutant has been characterized as a mouse model of schizophrenia (Cox et al., 2009; Feng et al., 2008), the patient with HPS-7 did not show symptoms related to schizophrenia (Li et al., 2003). No pathological mutation of the HPS7/DTNBP1 gene has been identified yet in patients with schizophrenia.


Prolonged bleeding often requires multiple platelet transfusions, and the fibrotic lung disease may lead to death in midlife.


There is presently no cure for HPS. Only symptomatic (e.g., sunscreen to avoid sunburn, platelet transfusion and use of desmopressin in the correction of prolonged bleeding) treatments for the disease exist. Stem cell therapy may be promising in alleviating symptoms such as bleeding and visual loss.


The gold standard of HPS is the absence of platelet-DG upon electron microscopy (EM). Symptoms of hypopigmentation and bleeding support the diagnosis. Molecular diagnoses are now available with the identification of nine HPS genes in humans. Chediak–Higashi syndrome (CHS, OMIM #214500) exhibits similar defects on the biogenesis of LROs due to the mutation on the CHS1/LYST gene (Barbosa et al., 1996). Mortality of CHS in childhood often results from frequent bacterial infections due to immunodeficiency or from an ‘accelerated phase’ lymphoproliferation into the major organs of the body (Blume and Wolff, 1972). Patients exhibiting milder clinical phenotypes survive to adulthood but develop progressive and often fatal neurological dysfunction (Karim et al., 2002). Griscelli syndrome (GS, OMIM #214450) also presents with hypopigmentation, immunological impairment, lymphohistiocytosis, or defects in the central nervous system (Meeths et al., 2010), but lacks defects in platelet DG (Chintala et al., 2007). Griscelli syndrome is caused by mutation of GS1/MYO5A (Pastural et al., 1997), GS2/RAB27A (Menasche et al., 2000), or GS3/MLPH (Menasche et al., 2003). Molecular diagnosis and EM examination of platelet-DG in patients with CHS or GS allow accurate differentiation from HPS (Table 1).

Table 1. Syndromic dysgenesis of lysosome-related organelles
Specialized LROsDysfunctionSyndromes
  1. CHS, Chediak–Higashi syndrome; GS, Griscelli syndrome; HPS, Hermansky–Pudlak syndrome; LRO, lysosome-related organelles.

MelanosomesOculocutaneous albinism (hypopimentation)HPS, CHS, GS
Platelet granulesBleeding diathesisHPS, CHS
Synaptic vesicles

Abnormal behaviors

Neurological symptoms

Lytic granulesImmunodeficiencyHPS-2, CHS, GS
Azurophil granulesNeutropeniaHPS-2, CHS
Lamellar bodiesLung fibrosisHPS-1, HPS-4

Mutations in HPS genes

Through positional candidate cloning, the first human HPS gene, HPS1, was identified in 1996 (Oh et al., 1996). This prompted the identification of the first murine HPS gene, Hps1/ep (Gardner et al., 1997; Spritz, 2000), and the cloning of 14 other HPS genes in mouse and eight human HPS genes thereafter (Table 2). Currently, proteins encoded by these human or murine HPS genes fall into several protein complexes in regulating vesicle trafficking in the endo-lysosomal system as summarized in several reviews (Di Pietro and Dell'Angelica, 2005; Huizing et al., 2008; Li et al., 2004; Sitaram and Marks, 2012; Wei, 2006). That is HPS1 and HPS4 in BLOC-3; AP3B1/HPS2 and AP3D in AP-3; HPS3, HPS5, and HPS6 in BLOC-2; HPS7, HPS8, HPS9, MUTED and CNO in BLOC-1. VPS33A is a subunit of HOPS. RABGGTA is the α-subunit of Rab geranylgeranyl transferase which is involved in the prenylation of Rab proteins. KXD1 is a BLOC-1 interactor that likely causes mild-form HPS when mutated (Yang et al., 2012). The cloning history of these HPS genes is listed in Table 2.

Table 2. The identified nine human and 15 mouse HPS genes
HPS subtypeHuman locusMouse mutantProtein functionReferences of cloning
  1. HPS, Hermansky–Pudlak syndrome. KO, knockout. BLOC-1, biogenesis of lysosome-related organelles complex-1. BLOC-2, biogenesis of lysosome-related organelles complex-2. BLOC-3, biogenesis of lysosome-related organelles complex-3. AP-3, adaptor protein complex-3. HOPS, homotypic fusion and protein sorting complex.

HPS-1HPS1pale-ear (ep)BLOC-3 subunitGardner et al. (1997), Oh et al. (1996)
HPS-2 HPS2/AP3B1 pearl (pe)AP-3 subunitDell'Angelica et al. (1999), Feng et al. (1997)
HPS-3HPS3cocoa (coa)BLOC-2 subunitAnikster et al. (2001), Suzuki et al. (2001)
HPS-4HPS4light-ear (le)BLOC-3 subunitSuzuki et al. (2002)
HPS-5HPS5ruby-eye 2 (ru2)BLOC-2 subunitZhang et al. (2003)
HPS-6HPS6ruby-eye (ru)BLOC-2 subunitZhang et al. (2003)
HPS-7HPS7/DTNBP1sandy (sdy)BLOC-1 subunitLi et al. (2003)
HPS-8 HPS8/BLOC1S3 reduced pigmentation (rp)BLOC-1 subunitMorgan et al. (2006), Starcevic and Dell'Angelica (2004)
HPS-9 HPS9/PLDN pallid (pa)BLOC-1 subunitCullinane et al. (2011a), Huang et al. (1999)
MUTED muted (mu)BLOC-1 subunitZhang et al. (2002a)
CNO cappuccino (cno)BLOC-1 subunitCiciotte et al. (2003)
KXD1 Kxd1-KO BLOC-1 interactorYang et al. (2012)
AP3D mocha (mh)AP-3 subunitKantheti et al. (1998)
VPS33A buff (bf)HOPS subunitSuzuki et al. (2003b)
RABGGTA gunmetal (gm)Rab geranylgeranyl transferase alpha subunitDetter et al. (2000)


The HPS1 gene is located on chromosome 10q24.2. It contains 20 exons (NCBI RefSeq: NM_000195), encoding a 700-aa HPS1 protein. There are three other transcription variants. Thirty-one alleles that cause HPS-1 have been identified and listed in the HPSD database. Most of the HPS1 gene mutations are frameshift mutations or nonsense mutations to produce truncated HPS1 proteins that disrupt the function of the HPS1 protein (Hermos et al., 2002; Oh et al., 1996, 1998). HPS1, together with HPS4, is an obligate subunit of BLOC-3. Loss of either subunit results in destabilization of the remaining subunits (Suzuki et al., 2002). Two missense mutations (p.L239P and p.L668P) have been reported. Overexpression of L668P-mutant HPS1 protein in HPS1-null melanocytes did not restore the stability of endogenous HPS4, suggesting this missense substitution is pathologic (Ito et al., 2005). Interestingly, the c.1932delC mutation leads to a longer HPS1 protein in which a novel 79-residue peptide replaces the wild-type 56-residue peptide after the mutation site at D644 (Wei et al., 2009). A similar elongated HPS1 protein is predicted for the c.1885delC mutation (Wei et al., 2011). In our Western blots, the elongated HPS1 protein is absent (Figure 1), indicating that the extension destabilizes the protein and is pathologic. The patient who carries the homozygous c.1932delC mutation shows typical OCA symptoms and the absence of platelet-DG (Figure 1), a gold standard for the diagnosis of HPS.

Figure 1.

Feature of a Chinese HPS-1 patient with the c.1932delC homozygous mutation. (A) The 2-yr-old girl with HPS1 who was diagnosed with a homozygous c.1932delC mutation in the HPS1 gene, shows hypopigmentation in skin and hair (Wei et al., 2009). (B) Hypopigmentation in the retinas of this HPS-1 patient (lower panel) compared with normal pigmented retinas (upper panel; Wei et al., 2009). (C) Lack of dense granules in the patient's whole-mount platelets. This electron microscopy (EM) examination was done by Dr. Ling Yang and Ms. Zhe Zhang. (D) The homozygous c.1932delC mutation of the HPS1 gene leads to the loss of the 80 kD HPS1 protein, without the expected larger band of the predicted elongated HPS1 protein on the blot in the patient's platelets. The monoclonal mouse HPS1 antibody used in this immunoblotting assay was a gift of Dr. Richard A. Spritz. This assay was assisted by Ms. Zhe Zhang. This study was approved by the IRB of Beijing Tongren Hospital. The subjects in this study gave written informed consent. HPS, Hermansky–Pudlak syndrome.


The HPS2 gene is located on chromosome 5q14.1. It contains 27 exons (NCBI RefSeq: NM_003664), encoding a 1094-aa AP3B1 protein, the β-subunit of the ubiquitous AP-3 complex (β3A). Eleven alleles that cause HPS-2 have been identified and listed in the HPSD database. Most of the HPS2 gene mutations are frameshift mutations or nonsense mutations to produce truncated AP3B1 proteins that disrupt the function of the AP3B1 protein, leading to the complete absence of β3A subunit and the destabilization of other AP-3 subunits (Clark et al., 2003; Dell'Angelica et al., 1999; Fontana et al., 2006; Huizing et al., 2002).


The HPS3 gene is located on chromosome 3q24. It contains 17 exons (NCBI RefSeq: NM_032383), encoding a 1004-aa HPS3 protein. Eight alleles that cause HPS-3 have been identified and listed in the HPSD database. Most of the HPS3 gene mutations are frameshift mutations or splicing mutations to produce truncated HPS3 proteins that disrupt the function of the HPS3 protein and BLOC-2 (Anikster et al., 2001; Boissy et al., 2005; Huizing et al., 2001a).


The HPS4 gene is located on chromosome 22q12.1. It contains 14 exons (NCBI RefSeq: NM_022081), encoding a 708-aa HPS4 protein. Four alternative transcription variants exist that differ in the 5′-UTR and coding regions compared to NM_022081. Thirteen alleles that cause HPS-4 have been identified and listed in the HPSD database. Most of the HPS4 gene mutations are frameshift mutations or nonsense mutations to produce truncated HPS4 proteins that disrupt the function of the HPS4 protein and BLOC-3 (Anderson et al., 2003; Bachli et al., 2004; Carmona-Rivera et al., 2011; Suzuki et al., 2002).


The HPS5 gene is located on chromosome 11p15.1. It contains 23 exons (NCBI RefSeq: NM_181507), encoding a 1129-aa HPS5 protein. Two alternative transcription variants exist that encode a 1015-aa HPS5 isoform. Eleven alleles that cause HPS-5 have been identified and listed in the HPSD database. Most of the HPS5 gene mutations are frameshift mutations that show severely decreased HPS5 mRNA, attributable to nonsense-mediated decay (Huizing et al., 2004; Zhang et al., 2003).


The HPS6 gene is located on chromosome 10q24.32. It contains only one exon (NCBI RefSeq: NM_024747), encoding a 775-aa HPS6 protein. Nine alleles that cause HPS-6 have been identified and listed in the HPSD database. Most of the HPS6 gene mutations are frameshift or nonsense mutations that disrupt the function of HPS6 protein and BLOC-2 (Huizing et al., 2009; Zhang et al., 2003).


The HPS7 or DTNBP1 gene is located on chromosome 6p22.3. It contains 10 exons (NCBI RefSeq: NM_032122), encoding a 351-aa dysbindin-1a protein. NM_183040 contains an additional segment in the coding region compared to NM_032122. The resulting 303-aa dysbindin-1b contains a shorter and distinct C-terminus compared to dysbindin-1a. NM_183041 contains an alternate splice site in the 5′ coding region and uses a downstream start codon, compared to NM_032122. The encoded 270-aa isoform dybindin-1c has a shorter N-terminus compared to dysbindin-1a. In addition, three dysbindin-2 isoforms and two dysbindin-3 isoforms were documented (Tang et al., 2009a; Talbot et al., 2009a). To date, only one homozygous nonsense mutation, p.Q103X, has been reported in a patient with HPS-7 (Li et al., 2003).


The HPS8 gene is located on chromosome 19q13.32. It contains only one exon (NCBI RefSeq: NM_212550), encoding a 202-aa BLOS3 protein. Two alleles that cause HPS-8 have been identified and listed in the HPSD database. No nonsense-mediated decay and destabilization of the BLOC-1 complex was observed to the p.S44X and p.Q150delC mutation (Cullinane et al., 2012; Morgan et al., 2006).


The HPS9 gene is located on chromosome 15q21.1. It contains five exons (NCBI RefSeq: NM_012388), encoding a 172-aa HPS9 protein. To date, only one homozygous nonsense mutation, p.Q78X, has been reported in a patient with HPS-9 (Cullinane et al., 2011a). The p.Q78X mutation does not cause nonsense- mediated decay directly but results in the skipping of exon3 (Cullinane et al., 2011a).

Mouse models of HPS

A major contribution of Dr. Richard T. Swank's laboratory was the collection, since the 1970s, of mouse mutants that mimic the human HPS phenotypes. Additional phenotypes such as susceptibility to anesthetics, protection from atherosclerosis, and otolith deficiency have been documented only in mouse HPS mutants as summarized in (Li et al., 2004; Swank et al., 1998). The characterization of more than a dozen mouse HPS mutants (Swank et al., 1998) led to a series of successful identifications of murine and human HPS genes (Li et al., 2004; Table 2). Currently, the 15 cloned mouse HPS genes are known to reside in several HPS Protein Associated Complexes (HPAC, shown in Table 2 and Figure 2) to mediate the biogenesis of LROs.

Figure 2.

Illustration of the HPS protein associated complexes (HPAC). Seven HPACs are depicted based on the current understanding of the structural assembly and physical interactions described in the text. BLOC-1 is assembled linearly connected by two subcomplexes (BLOS1-pallidin-cappuccino and BLOS2-dysbindin-snapin), with muted and BLOS3 overhung. KXD1 is a BLOC-1 interactor bound to BLOS1. In BLOC-2, HPS3, HPS5, and HPS6 interact with each other. HPS1 and HPS4 are tightly bound in BLOC-3. In the HOPS complex, VPS18 connects the head (VPS16-VPS33A-VPS41) and tail (VPS11 and VPS39). The ubiquitous AP-3 complex contains the β3A, δ, μ3A and σ3 subunits. The core Rab GGTase II enzyme consists of α and β subunits. In the RabGGTase II holoenzyme, REP-1 (or component A) binds unprenylated Rab proteins and then presents them to the catalytic Rab GGTase II for the geranylgeranyl transfer reaction. The protein names with a star sign (*) indicate mutations in human and mouse HPS, those with a pound sign (#) indicate mutations in mouse HPS only. A question mark on the RAB38 indicates an unresolved HPS protein. HPS, Hermansky–Pudlak syndrome.

With the discovery of murine and human HPS genes, three biogenesis of lysosome-related organelles complexes (BLOC-1, BLOC-2, and BLOC-3) have been defined. That is, pallidin, muted, dysbindin, cappuccino, snapin, BLOS1, BLOS2, and BLOS3 in BLOC-1 (Ciciotte et al., 2003; Falcon-Perez et al., 2002; Gwynn et al., 2004; Li et al., 2003; Starcevic and Dell'Angelica, 2004); HPS3, HPS5, and HPS6 in BLOC-2 (Di Pietro et al., 2004; Gautam et al., 2004; Zhang et al., 2003); and HPS1 and HPS4 in BLOC-3 (Chiang et al., 2003; Martina et al., 2003; Nazarian et al., 2003; Suzuki et al., 2002). The biochemical features and assembling machineries of these BLOC complexes remain to be defined, although some pioneering studies have revealed binding domains in building these BLOCs (Dell'Angelica, 2004; Li et al., 2007) and the linear assembly of the BLOC-1 complex in vitro (Lee et al., 2012). Together with the well-known AP-3 (adaptor protein complex-3) and HOPS (homotypic fusion and protein sorting complex) complexes, the BLOC complexes function in endo-lysosomal trafficking. Emerging evidence has shown that these complexes direct cargoes from either de novo synthesis or endocytosis into lysosomes and LROs. In addition, whether there is a master regulator to coordinate the action of these complexes remains unknown. A key to understanding LRO biogenesis is to define the behaviors of these interacting complexes. An intriguing question is whether these complexes act synergistically or sequentially on cargo transport. Double or multiple mouse mutants played a pivotal role in dissecting these interactions as evidenced by epistatic or synergistic effects on coat color or LRO phenotypes (Gautam et al., 2006; Hoyle et al., 2011). At the cellular level, the mouse HPS mutants provide powerful tools for the dissection of cargo-specific endo-lysosomal-trafficking pathways in different tissues.

As revealed by spontaneous murine HPS mutants, one would expect the development of HPS when generating knockout mutants for the remaining subunits of the HPACs. While the mutants of known subunits of BLOC-2 and BLOC-3 are murine HPS models (Li et al., 2004), it is unknown whether mutation of the genes encoding snapin, BLOS1, and BLOS2 in the BLOC-1 complex would cause typical HPS. In contrast, the snapin knockout (KO) mice died at the perinatal stage, which is unlike other BLOC-1 mutants and showed developmental defects of the central nervous system (Tian et al., 2005; Zhou et al., 2011). This suggests that snapin may play extra roles independent of BLOC-1. Whether the BLOS1 or BLOS2 knockout mice exhibit typical HPS phenotypes with comparable survival remains to be investigated. Interestingly, multiple isoforms of dysbindin have been shown both in human and mouse tissues (Talbot et al., 2009). Studies have shown the different distribution pattern of these isoforms in developmental stages and in sub-brain regions and sub-synaptic regions (Ito et al., 2010; Talbot et al., 2011; Tang et al., 2009a). The involvement of dysbindin in the dystrobrevin complex (Benson et al., 2001) and WAVE2-Abi-1 complex (Ito et al., 2010) has raised the question whether all these isoforms function in a BLOC-1-dependent manner.

The AP-3 complex is a heterotetramer composed of two large adaptins (AP3D1/δ and AP3B1/β3A or AP3B2/β3B), a medium adaptin (AP3M1/μ3A or AP3M2/μ3B), and a small adaptin (AP3S1/σ3A or AP3S2/σ3B). There exist two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising AP3D1-AP3B1-AP3M1-AP3S1 (or AP3S2) subunits and a brain-specific AP-3 complex containing AP3D1-AP3B2-AP3M2-AP3S1 (or AP3S2) subunits as summarized in a recent review (Dell'Angelica, 2009). In mice, only mutation of the Ap3b1 (in pearl mice) or Ap3d1 (in mocha mice) have been shown to present HPS phenotypes (see Table 2). Knockout of the neuron-specific Ap3b2 or Ap3m2 results in neurological impairments but not HPS (Nakatsu et al., 2004; Newell-Litwa et al., 2009; Seong et al., 2005). This leads to the notion that tissue-specific complexes are formed to execute special physiological functions.

The class C Vps complexes (HOPS and CORVET) are involved in homotypic fusion and tethering during endosomal trafficking (Nickerson et al., 2009). Both HOPS and CORVET complexes share the four Vps proteins (class C core), VPS11-VPS16-VPS18-VPS33. The HOPS complex contains in addition two Rab-binding proteins, VPS41 and VPS39, whereas the CORVET complex has the VPS41 homolog VPS8 and the VPS39 homolog VPS3. The CORVET and HOPS complexes interconvert through two intermediate complexes consisting of the class C core bound to VPS39-VPS8 or VPS3-VPS41 (Peplowska et al., 2007). In the HOPS complex, the large head contains VPS41, VPS33, and VPS16, whereas Vps39 is found in the tip of its tail, with VPS11 and VPS18 connecting the head and tail (Brocker et al., 2012). VPS33 is a Sec1-/Munc18-like protein that interacts with SNAREs. In metazoans, two homologs, VPS33A and VPS33B, are present. It is uncertain whether VPS33B is a component of the COVERT complex (Zlatic et al., 2011), while VPS33A is a part of the HOPS complex (Sriram et al., 2003). Mutation of Vps33a in the bf mice leads to HPS with additional neurological lesions, although the underlying mechanism leading to Purkinje cell loss and neurological atrophy is unknown (Chintala et al., 2009; Suzuki et al., 2003b). A mutation in human VPS33B causes arthrogryposis-renal dysfunction-cholestasis syndrome but not HPS (Gissen et al., 2004). Again, this suggests that distinct mammalian Vps-C complexes function differently.

The HPS mouse model gunmetal (gm) is deficient in the α-subunit of Rab GGTase II (RABGGTA; Detter et al., 2000). Together with the β-subunit and an escort protein, REP-1, RABGGTA adds two geranyl 10-carbon isoprenoid groups to the C-termini of Rab proteins (Anant et al., 1998). In gm mutant, the prenylation of Rab proteins (such as Rab27a, 11a, and 4) is deficient in platelets and melanocytes (Zhang et al., 2002b), which may explain the defects in the biogenesis of platelet granules and melanosomes, thus mimicking the symptoms of HPS. Currently, no RABGGTA mutation has been reported in patients with HPS or storage pool deficiency (Li et al., 2000). However, mutations in the CHM gene that encodes REP-1 are a cause for choroideremia (also known as tapetochoroidal dystrophy). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium, and retina (Sankila et al., 1992). Defective Rab prenylation and depigmentation occur in Chm knockout mice (Tolmachova et al., 2006).

RAB38 forms a complex with VARP in mediating the melanosomal transport of TYRP1 (Tamura et al., 2009; Wang et al., 2008). Mutation of the melanosomal protein RAB38 in chocolate (cht) mice causes dilution in coat color (Loftus et al., 2002) and ocular hypopigmentation (Brooks et al., 2007), suggesting that cht is a mouse model of OCA. In addition, defects in melanosomes (Brooks et al., 2007) and lamellar bodies (LBs; Osanai et al., 2008) were observed in cht mice, suggesting that RAB38 is a candidate HPS gene affecting multiple LROs (Brooks et al., 2007; Osanai and Voelker, 2008). Consistent with this possibility, the rat RAB38 is null in Fawn-Hooded and Tester-Moriyama rats which mimic the human HPS phenotype (Oiso et al., 2004). Other evidence to show the involvement of RAB38 in the development of HPS is the interactions between RAB38 and BLOC-1, BLOC-2, and AP-3, which likely transport the cargoes of BLOC-2, AP-3, and AP-1 into melanosomes (Bultema et al., 2012). In addition, BLOC-3 has been shown to function as a guanine nucleotide exchange factor for RAB38 and RAB32 (Gerondopoulos et al., 2012). Taken together, these data suggest that RAB38 and RAB32 function with other HPS protein complexes, implicating the loss-of-function of RAB38 or RAB32 may develop similar phenotypes as HPS. However, no prolonged bleeding times or blood defects occur in cht mice (Brooks et al., 2007; Loftus et al., 2002). One possible explanation is a hypermorphic effect in cht mice. The existing mutant hydrophilic RAB38 (Osanai et al., 2008) may function in platelets without affecting the biogenesis of DG. Another explanation is redundant function of a RAB38 homolog, RAB32, in platelets (Wasmeier et al., 2006). In a recent study, RAB38 and RAB32 are involved in the cargo vesicle fusion with mature organelles during the biogenesis of platelet-DG (Ambrosio et al., 2012). Currently, no mutation of the RAB38 gene has been reported in patients with HPS or OCA (Brooks et al., 2007; Suzuki et al., 2003a).

Misty (m) mice show generalized hypopigmentation and prolonged bleeding times similar to HPS mouse mutants (Sviderskaya et al., 1998; Swank et al., 1998), but no evidence of a generalized LRO anomaly (Blasius et al., 2009). Thus, the mutation of Dock7 (a Rho family guanine nucleotide exchange factor) in misty mice (Blasius et al., 2009) is unlikely to cause murine HPS. The subtle gray (sut) mouse was regarded as a model for a mild form of HPS (Swank et al., 1996, 1998). However, the hypopigmentation is mainly caused by the reduction in pheomelanin production due to the mutation of the Slc7a11 gene which encodes the functional subunit of the cystine/glutamate antiporter, xCT (Chintala et al., 2005). Although the function of xCT in the biogenesis of platelet-dense granule has not been intensively studied, no generalized LRO anomaly in sut mice has been described, excluding it as a typical mouse HPS model. The ashen (ash) line maintained at Roswell Park Cancer Institute (referred as ash-Roswell) that was regarded as a mouse model of HPS (Li et al., 2004; Wilson et al., 2000) has been identified to be a double mutant with mutations in both the Rab27a gene and the Slc35d3 gene (Chintala et al., 2007; Wilson et al., 2000). The deficiency in Rab27a causes a defect in melanosomal transport which leads to hypopigmentation (Wilson et al., 2000), while the deficiency of Slc35d3 leads to defects in the biogenesis of platelet-DG (Chintala et al., 2007; Meng et al., 2012). The Rab27a mutation does not cause defects in platelet-DG or prolonged bleeding (Barral et al., 2002). In contrast, hypopigmentation is not seen in the Roswell (ros)-mutant mice, which carry only the Slc35d3 mutation. SLC35D3 may not be expressed in melanocytes (our unpublished data). Thus, the identified HPS mouse models have been updated to 15 lines as listed in Table 2.

HPS genes in the biogenesis of lysosome-related organelles

Lysosome-related organelles

Lysosomes are membrane-bound cytoplasmic organelles that are found in all mammalian cells and contain hydrolases and lipases required for protein and membrane degradation. They are characterized by soluble acid-dependent hydrolases and a set of highly glycosylated integral membrane proteins such as lysosome-associated membrane proteins (LAMPs). Many properties of lysosomes such as acidic lumenal pH, LAMPs, and high intralumenal Ca2+ concentrations are likely shared by a group of cell type-specific compartments referred to as ‘LROs’, which include melanosomes, platelet-DG, Weibel–Palade bodies (WPB), and large dense core vesicles (Table 3 and Figure 3; Li et al., 2004). In addition to lysosomal proteins, these organelles contain cell type-specific components that are responsible for their specialized functions (Dell'Angelica et al., 2000; Raposo et al., 2007). Lysosome-related organelles feature cell type-specific morphology and functions and may undergo regulated secretion (also called secretory lysosomes). They can co-exist with lysosomes in some cells like melanocytes and platelets.

Table 3. Lysosome-related Organelles (LROs)
OrganellesTissue distribution
Secretory lysosomesUbiquitous
Platelet-dense granulesPlatelets
Weibel–Palade bodiesEndothelial cells
Large-dense core vesiclesAdrenal chromaffin cells
Synaptic vesiclesNeurons
Insulin granulesPancreatic islets
Lamellar bodiesAlveolar type II epithelial cells
Lytic granulesNK cells, Cytotoxic T lymphocytes
MHC-II compartmentsAntigen-presenting cells
Basophilic granulesMast cells
Azurophilic granulesNeutrophils, Eosinophils
Osteoclast granulesOsteoclasts
Renin granulesJuxtaglomerula cells
Otic vesiclesInner ear cells
Fusiform vesiclesUrothelial umbrella cells
Figure 3.

Representative electron microscopic pictures of lysosome-related organelles (LROs) in mouse tissues. (A) Melanosomes in retinal pigment epithelium (RPE) and choroid. (B) Dense granules (DGs) in whole-mount platelet. (C) Weibel–Palade bodies (WPBs) in endothelial cells in longitudinal section (upper) and transverse section (lower). (D) Large-dense core vesicles (LDCVs) in adrenal chromaffin cells. Arrows in the images indicate the representative LROs.

Cargo-specific trafficking to lysosomes, melanosomes, and other LROs

HPS genes in the biogenesis of lysosomes

Lysosomal biogenesis has puzzled scientists since the definition of lysosome. A transcription factor EB (TFEB) has been reported to be the master regulator of lysosomal biogenesis (Sardiello et al., 2009). Putative promoter regions of HPS genes may be regulated by TFEB or other transcription factors (Palmieri et al., 2011; Stanescu et al., 2009). The well-known function of lysosomes is the degradation of transported cargoes via the endo-lysosomal-trafficking system. However, its function is broadened especially in autophagy, phagocytosis, and exocytosis as summarized in a recent review (Boya, 2012). How constitutive membrane proteins and luminal proteins are directed into lysosomes is not well defined, although accumulating data have revealed that this process may utilize the machinery of endo-lysosomal trafficking. In HPS, the function of lysosomes is disturbed as evident in abnormal secretion of kidney lysosomal enzymes in HPS mouse mutants (Swank et al., 1998). However, the exact mechanism is unclear. In our hypothesis, during lysosomal biogenesis, in concert with the expression of lysosomal proteins under the control of TFEB, the lysosomal-trafficking HPS proteins are likely involved in coordinating the transport and assembly of the lysosomal proteins into lysosomes.

Lysosome-associated membrane proteins are known to function in the maintenance of lysosomal structures. The tetraspanin CD63 or LAMP3 is endocytosed and directed to late endosomes and lysosomes where it functions as a constitutive lysosomal membrane protein. AP-3 and BLOC-1 likely transport a cohort of lysosomal membrane proteins including CD63 into lysosomes. Accumulation of CD63 on the cell surface is seen in AP-3 or BLOC-1 knockdown cells, but with normal distribution in BLOC-2 or BLOC-3 knockdown cells (Di Pietro et al., 2006). The distribution of another LAMP protein, LAMP1, is altered in a similar way (Salazar et al., 2006). Although missorted LAMPs are present on the plasma membrane in AP-3- or BLOC-1-deficient cells, a majority of these proteins are still present in bona fide lysosomes. This may explain why the existing BLOC-1- or AP-3-mutant mice are viable without apparent lesions in tissues like liver and heart. BLOC-1 and AP-3 either facilitate delivery of a cohort of lysosomal membrane proteins to lysosomes or enhance the efficiency of lysosomal delivery. A more plausible mechanism of the roles of BLOC-1 and AP-3 in lysosomal protein trafficking is that they coordinate LAMPs for degradation in conventional lysosomes and regulate their constitutive transport to secretory lysosomes. Similarly, in neurons, two other well-known lysosomal proteins and AP-3 cargoes, PI4KIIα and VAMP7-TI, are increased in synaptic vesicles (SVs; Newell-Litwa et al., 2009) but decreased in steady-state levels (Salazar et al., 2006) in either AP-3- or BLOC-1-deficient neurons. When the sorting to lysosomes is disrupted, the cargoes may be missorted to SVs or vice versa (Newell-Litwa et al., 2009).

HPS genes in the biogenesis of melanosomes

The study of melanosomal biogenesis provides an excellent example of LRO biogenesis (Marks and Seabra, 2001; Raposo and Marks, 2002). PMEL is thought to be a key molecule in melanosomal assembly (Theos et al., 2006). Other melanosomal components involved in melanin synthesis include tyrosinase (TYR), OCA2, TYRP1, SLC45A2, SLC24A5, and DCT/TYRP2 and ATP7A (Ito and Wakamatsu, 2011; Setty et al., 2008). How these melanosomal proteins are transported into melanosomes is beginning to be understood. PMEL is sorted into immature melanosomes, which is dependent on AP-2 (Robila et al., 2008) and CD63 (van Niel et al., 2011). TYR, OCA2, and TYRP1 all contain acidic dileucine (LL)-based consensus motifs that can be recognized by AP-1, AP-2, or AP-3. Although DCT lacks the cytoplasmic LL-motif, it binds to AP complexes (Bonifacino and Traub, 2003), but how it is sorted into melanosomes is unknown.

The HPACs have been known to mediate the transport of melanosomal proteins. These HPACs act as adaptors to cargo proteins during this transport as summarized in a recent review (Sitaram and Marks, 2012). TYR is sorted into the AP-3 buds of vacuolar endosomes, where TYR is directed into melanosomes via a BLOC-1-independent pathway (Theos et al., 2005). BLOC-2 and RAB38 may act downstream of this AP-3-dependent pathway (Bultema et al., 2012). In addition, a portion of TYR that is sorted into AP-1 buds may compensate for its targeting to melanosomes when AP-3 is deficient (Theos et al., 2005). In contrast, OCA2 is sorted into AP-1 or AP-3 buds and thereafter is directed by BLOC-1 into mature melanosomes (Sitaram et al., 2009, 2012). Likewise, BLOC-2 and RAB38 act downstream of this BLOC-1-dependent pathway (Bultema et al., 2012; Setty et al., 2007). However, TYRP1-sorting signals interact with AP-1 but not AP-3 (Theos et al., 2005). Therefore, TYRP1 is sorted into mature melanosomes in a similar way as OCA2 via the BLOC-1-dependent pathway, but independent of AP-3 (Huizing et al., 2001b; Setty et al., 2007). Similar to TYRP1, the copper transporter, ATP7A, is sorted into melanosomes via the BLOC-1-dependent pathway (Setty et al., 2008).

How other melanosomal proteins such as GPR143, MART-1, and the other two transporters (SLC45A2 and SLC24A5) are sorted into melanosomes remains unclear. On the other hand, although BLOC-3 has been described in regulating melanosomal biogenesis (Huizing et al., 2008; Li et al., 2004), its exact mechanism in melanosomal protein trafficking is unknown. It has been suggested that BLOC-3 acts as the RAB9 effector to regulate melanosomal biogenesis (Kloer et al., 2010). A recent study has shown that BLOC-3 acts as a RAB38/32 guanine nucleotide exchange factor. BLOC-3 deficiency results in mislocalization of RAB38 and RAB32 and reduction of pigmentation. It is suggested that proteolytic maturation of PMEL and melanosomal biogenesis may be affected when this BLOC-3-/RAB38-dependent pathway is disrupted (Gerondopoulos et al., 2012). It is unknown whether BLOC-3 itself acts as an adaptor for melanosomal protein trafficking. Finally, the HOPS complex may function in the docking of AP-3-coated vesicles during melanosomal biogenesis through the interaction between VPS41 and AP3D (Angers and Merz, 2009; Rehling et al., 1999).

HPS genes in other non-melanosomal LROs

The biogenesis of melanosomes has provided important clues to understand the sorting mechanisms in the biogenesis of non-melanosomal LROs. However, whether the non-melanosomal LROs employ similar cargo sorting mechanisms regulated by HPS genes requires additional study. As LROs exhibit tissue-specific compositions and functions, dissecting the cargo-specific sorting mechanism is the first step to determine whether a cargo uses a pathway similar to that in melanosomal biogenesis. The fact that BLOC-1 and AP-3 function together seems to be more general in different cell types such as neurons (Newell-Litwa et al., 2009), platelets (Meng et al., 2012), and Hela cells (Borner et al., 2006).

Synaptic vesicles (SVs): In neurons, two synaptic vesicle components, ZnT3 and VAMP2, are similarly sorted into SVs by the neuronal AP-3 isoform. However, lysosomal transport mediated by the ubiquitously expressed AP-3 isoform and BLOC-1 complex functions mainly in lysosomal targeting of AP-3 cargoes such as PI4KIIα and VAMP7-TI. When the ubiquitous AP-3 or BLOC-1 is defective, cargoes that normally are sorted to lysosomes are routed to SVs and vice versa (Newell-Litwa et al., 2007, 2009; Salazar et al., 2009). A chloride channel, CIC-3, is packed in the synaptic-like microvesicles (SLMVs) along with the ZnT3 mediated by AP-3 (Salazar et al., 2004). In addition, loss of AP-3 results in increased synaptic vesicle size in the hippocampal dentate gyrus, as opposed to decreased vesicle size in the striatum. BLOC-1 likely contributes to these region-specific effects of AP-3 (Newell-Litwa et al., 2010). Defects in synaptic vesicle size may lead to abnormal neurotransmission (Chen et al., 2008) and therefore the development of abnormal behaviors as shown in dysbindin-null-mutant mice (Feng et al., 2008). How the HPS genes regulate cargo transport in the biogenesis of SVs is uncertain.

Large-dense core vesicles (LDCVs): The biogenesis of LDCVs in neuroendocrine cells is another good model to study LRO biogenesis. Large-dense core vesicles bud from the trans-Golgi network (TGN), and the aggregation of granins drives their formation. The mature LDCV release their contents (e.g., neuropeptides) under regulated secretion. During LDCV biogenesis, sorting mechanisms are important to ensure proper cargo assembly into mature and condensed vesicles [reviewed by (Tooze et al., 2001)]. AP-3 is likely involved in cargo sorting into immature LDCVs. Lack of the ubiquitous AP-3 leads to a dramatic increase of vesicle size and releasing quantal size (Grabner et al., 2006). In the absence of AP-3, LDCVs contain less synaptagmin-1, CGA and SgII, which may affect LDCV morphology (enlarged size and decreased number; Asensio et al., 2010). Similarly, the LDCVs in adrenal chromaffin cells of the dysbindin-null mutant mice are reduced in number and increased in vesicle size, leading to reduced secretion events and increased quantal size (Chen et al., 2008). The enlarged size of LDCV might represent immature LDCVs. AP-3 or BLOC-1 may be involved in sorting LDCV cargoes into immature LDCVs or sorting unnecessary cargoes out of immature LDCVs. Deficiency in AP-3 or BLOC-1 may block maturation of LDCVs. Interestingly, it has been reported that chromaffin cells have two populations of LDCVs with distinct secretory properties, representing two distinct synthetic pathways for LDCV biogenesis or different stages of biogenesis (Grabner et al., 2005). However, the underlying mechanism of the biogenesis of these two populations awaits further investigation.

Dense granules (DGs): During platelet activation, DGs release small molecules like ATP, ADP, serotonin, and calcium for blood clotting. The loss of DGs is regarded as the gold standard in diagnosing HPS (Huizing et al., 2008). However, the underlying mechanism of DG biogenesis is not clear. SLC35D3 is a key component of DGs. Loss of SLC35D3 causes lack of DGs in platelets (Chintala et al., 2007). A recent report has shown that SLC35D3 may serve as either a cargo of DGs or a sorting molecule for DG cargoes. Loss of BLOC-1 or AP-3 shows a reduction of SLC35D3. However, SLC35D3 occurs at almost normal levels in BLOC-3-deficient platelets. This suggests that BLOC-1 and AP-3 may function together in sorting SLC35D3 into DGs (Meng et al., 2012). Other defects of DG components are difficult to define as DGs are absent or empty in patients with HPS. KXD1 is a BLOC-1 interactor. Kxd1 knockout mice exhibit reduced number of platelet DGs (Yang et al., 2012). This mouse mutant may offer a resource to uncover DG components defective in BLOC-1 inefficiency.

Weibel–Palade bodies (WPBs): WPBs are LROs specificly localized in endothelial cells. After stimulation, WPBs quickly release their contents (such as von Willebrand factor (vWF), interleukin-8 (IL-8), P-selectin, and endothelin) which play important roles in various physiological responses such as hemostasis, inflammation, angiogenesis, and wound healing. The involvement of HPS genes in regulating WPB biogenesis has been reviewed (Metcalf et al., 2008). In this multi-step maturation model, two WPB components, P-selection and vWF, are sorted to the immature WPB by AP-1 at the trans-Golgi network (TGN; Lui-Roberts et al., 2005). CD63 sorting to the mature WPB is mediated by AP-3 (Harrison-Lavoie et al., 2006), while Rab27A and Rab3D are further directed to the mature WPB by unknown mechanisms (Hannah et al., 2003; Knop et al., 2004). Whether the BLOC complexes and HOPS complex are involved in WPB biogenesis is still unknown. Together with the defects in platelet DG, defects in the WPB biogenesis may contribute to the bleeding tendency observed in patients with HPS.

Cytolytic granules (CGs): HPS genes may also regulate the biogenesis of CGs in cytotoxic T lymphocytes (CTLs) and NK cells. In patients lacking AP-3, granule polarization is defective, thus CTL secretion is severely impaired (Clark et al., 2003). In mouse mutants deficient in Rab27a and Rabggta, CTL secretion is also impaired (Stinchcombe et al., 2001). However, the CGs may not be affected in CTLs deficient in BLOC-1, BLOC-2, BLOC-3, and HOPS (Bossi et al., 2005).

MHC-II compartments: MHC-II compartments in antigen-presenting cells undergo a process of maturation during antigen presentation. The biogenesis of these organelles is still a mystery. CD1B, but not other CD1 isoforms, binds to AP-3. In AP-3-deficient cells, CD1B fails to be targeted to lysosomes for antigen presentation. The defects in CD1B antigen presentation may explain the recurrent bacterial infections in patients with HPS-2 (Sugita et al., 2002). In conventional dendritic cells (DCs), AP-3 efficiently recruits Toll-like receptor (TLR) to phagosomes and is involved in MHC-II presentation of antigens internalized by phagocytosis. In AP-3-deficient DCs, export of the peptide: MHC-II complex to the cell surface was blocked (Mantegazza et al., 2012). AP-3, BLOC-1 and BLOC-2 are essential for plasmacytoid dendritic cell signaling through TLR7 and TLR9 (Blasius et al., 2010; Sasai et al., 2010).

Lamellar bodies (LBs): Lamellar bodies in alveolar type II (ATII) epithelial cells function in storage and secretion of surfactant which is important for lung function. LBs are abnormal in the Hps1/Hps2 double mutant. ATII cells and LBs of this mutant are greatly enlarged, and the LBs are engorged with surfactant (Guttentag et al., 2005; Lyerla et al., 2003). All these features are similar to the lung pathology described in patients with HPS-1. This mutant develops HPS-associated interstitial pneumonia (HPSIP) past 1 yr of age, which may be initiated by abnormal ATII cells and exacerbated by alveolar macrophage activation with elevated level of TGFβ1 (Wang and Lyerla, 2010). Likewise, the serum concentration of TGFβ1 correlates with the severity of interstitial lung disease in patients with HPS-2 (Gochuico et al., 2012). Aberrant surfactant trafficking and secretion may lead to the apoptosis of ATII cells, thereby causing the development of HPSIP (Mahavadi et al., 2010). In addition, the elevated TGFβ1 may trigger the activation of the epidermal growth factor receptor (EGFR) pathway to develop lung fibrosis (Madala et al., 2011). On the other hand, HPS genes may down-regulate the EGFR signaling pathway by promoting lysosomal degradation (Cai et al., 2010; Chirivino et al., 2011). Inefficient lysosomal degradation due to the loss of HPS proteins likely up-regulates the EGFR signaling to facilitate the development of lung fibrosis.

Acrosomes: The acrosome is a member of the LRO family (Moreno and Alvarado, 2006; Raposo et al., 2007). Similarly to other LROs, it undergoes a multi-step maturation process (Berruti and Paiardi, 2011). Cargoes are packaged into the pro-acrosomal granule (PG) from TGN and early endosomes. VPS54, a member of the Golgi associated retrograde protein complex, is likely involved in sorting cargoes from endosomes. The Vps54 mouse mutant, wobbler, lacks acrosomes and is infertile (Paiardi et al., 2011). By sorting-in and sorting-out mechanisms, PG is converted to pro-acrosome (PA) and the latter turns to be a mature acrosome. AP complexes, ESCRT complexes and motor proteins are likely involved in the acrosome biogenesis. Acrosomal defects have not been described yet in any of the HPS mouse mutants.

Other LROs: The pallid, muted, and mocha mice show absence of or abnormality in otoliths of the inner ear and reduced inner ear pigmentation, suggesting that HPS genes are involved in both otolith biogenesis and melanosome biogenesis in inner ear (Swank et al., 1991). However, the underlying mechanisms for otolith defects of these mouse mutants are unknown. The otic vesicle (OV) is likely another kind of LRO. Nascent otoliths are formed from a pool of precursor particles and tethered to cilia in the OV (Riley et al., 1997). Thus, OVs and cilia play important roles in otolith biogenesis. Manganese supplementation in pallid mice rescues the otolith defect but not hypopigmentation (Erway et al., 1971). In addition, transportation of manganese is delayed in pallid tissues (Cotzias et al., 1972). These results suggest that the otolith defects in these HPS mutants may be due to a defect in the trafficking of a manganese transporter or an unknown protein for which activity manganese is required in OVs.

Vps33a mutant mice (buff) show defects of uroplakin-delivering fusiform vesicles in urothelial umbrella cells. These vesicles were almost completely replaced by Rab27b-negative multivesicular bodies in mutant mice (Guo et al., 2009). In addition, mutation of Vps33a affects the cell surface expression level of RANKL and disrupts the trafficking of RANKL to the secretory lysosomes in osteoblasts or bone marrow stromal cells (Kariya et al., 2009).

Pancreatic islet beta-cells contain SLMVs. The sedimentation properties of beta-cell SLMVs are identical to those from PC12 cells. Neuronal AP-3b subunits are expressed in beta-cells. Inhibition of AP-3 prohibits the delivery of AP-3 cargoes to beta-cell SLMVs, suggesting that beta-cells share mechanisms for mediating the neuron-specific synaptic vesicle formation (Suckow et al., 2010). With the exploration of phenotypes in HPS, other LRO defects would be expected in a tissue-specific manner.

HPS genes in modulating signal transduction

Lysosomes function in the degradation of endocytosed ligands or receptors in order to turn off signal transduction in a proteosome-independent pathway. In HPS, when lysosomal degradation is impaired, the targeted receptors (such as dopamine receptor D2R, glutamate receptor NR2A) are often reinserted into the plasma membrane to increase their number (Ji et al., 2009; Tang et al., 2009b). Similarly in plants, we have shown that the deficiency in BLOC-1 leads to increase of plasma membrane expression of auxin effluxers PIN1 and PIN2, to up-regulate the auxin response and facilitate root development in Arabidopsis (Cui et al., 2010). However, deficiency of the AP-3 β subunit leads to the intracellular ectopic accumulation of PIN1 protein, causing root growth arrest of seedlings when growing in medium lacking sucrose (Feraru et al., 2010). The opposite phenotypes of BLOC-1 and AP-3 in Arabidopsis suggest that these two complexes may act differently in the recycling and degradation of PIN proteins. AP-3, HOPS, BLOC-1, and BLOC-2 have been involved in modulating signal transduction. The known effects on receptor trafficking in HPS are summarized in Table 4. Impaired signaling affects multiple cellular functions, such as neurotransmission, cell proliferation or differentiation, innate immune response, and organ development. We are at the beginning stages of establishing a link between lysosomal-trafficking and signal modulation. Modulation of signal transduction by HPS genes opens new avenues to study the mechanisms underlying developmental abnormalities, disrupted neurotransmission, and metabolic dysfunction.

Table 4. Abnormal receptor trafficking in HPS
  1. D2R, dopamine receptor 2; EGFR, epidermal growth factor receptor; MR5, M(5) muscarinic acetylcholine receptor; NR2A, NMDA receptor 2A; TLR, Toll-like receptor; IFN, interferon; HPS, Hermansky–Pudlak syndrome.

D2RIncreased on cell surface (Ji et al., 2009)   
Deltex/Notch receptor  Sort to lysosomal limiting membrane (Wilkin et al., 2008)Sort to lysosomal limiting membrane (Wilkin et al., 2008)
EGFRDelayed degradation (Cai et al., 2010)  Accumulation in endosomes and delayed degradation (Chirivino et al., 2011)
MR5  Decrease in the magnitude of presynaptic M5-mediated dopamine release potentiation in the striatum (Bendor et al., 2010) 
NR2AIncrease on cell surface (Tang et al., 2009b)   
TLRsImpaired TLR7/9 trafficking and type IIFN production (Blasius et al., 2010)Impaired TLR7/9 trafficking and type I IFN production (Blasius et al., 2010)

Impaired TLR7/9 trafficking and type I IFN production (Blasius et al., 2010; Sasai et al., 2010).

Impaired CD4(+) T cell activation and Th1 effector cell function (Mantegazza et al., 2012)


Perspectives and conclusions

During autophagy and phagocytosis, the formation of autolysosomes and phagolysosomes is a crucial functional step (He and Klionsky, 2009). The HOPS complex functions in autophagosome maturation (Liang et al., 2008). Snapin knockout mice exhibit phenotypes related to impaired autophagy or mitophagy (Cai and Sheng, 2011; Cai et al., 2010). AP-3 recruits TLR to phagosomes during antigen phagocytosis (Mantegazza et al., 2012). It would be interesting to see more studies of the possible involvement of HPS proteins in autophagy and phagocytosis to better understand neuronal cell death and immunodeficiency in HPS.

The application of exome sequencing on undiagnosed HPS samples provides a reasonable method of diagnosis and uncovering novel HPS genes. This has been successful in the identification of a patient with HPS-9 (Badolato et al., 2012) and an HPS-2-like patient (Cullinane et al., 2011b). The HPS genes revealed in mouse and other species are a useful resource when analyzing whole-exome sequencing data. On the other hand, patient-derived induced pluripotent stem cell technology and transdifferentiation technology may be applied to the treatment of HPS in recovering vision loss or bleeding or treating lung fibrosis in the future.

The discovery of HPS genes and studies of their functions has significantly expanded our knowledge of the control of endosomal-lysosomal trafficking. This knowledge will help us to better understand the transport of melanosomal proteins into melanosomes to synthesize melanin. In addition, determining their functions in the biogenesis of non-melanosomal organelles will provide a fascinating window into their tissue-specific cellular functions. It is always both fascinating and challenging to study the regulation of HPS genes and their involvement in differentiation of specialized cell types. The study of HPS has already expanded beyond hypopigmentation, especially emerging into the field of modulating signal transduction. This brings together organelle biology and signal transduction in the context of development.


This work was partially supported by grants from National Natural Science Foundation of China (31230046, 81101182), from Chinese Academy of Sciences (KSCX2-EW-R-05) and from The State Key Laboratory of Molecular Developmental Biology, China. We are very thankful to Dr. Richard T. Swank for his reading of this manuscript and critical comments. We apologize to the authors of relevant works that are not mentioned in this review.