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Keywords:

  • Yeast vacuole;
  • Drosophila pigment granule;
  • Lysosome biogenesis;
  • Protein trafficking;
  • Oculocutaneous albinism;
  • Dense body;
  • Vesicle

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The disorders known as Hermansky–Pudlak syndrome (HPS) are a group of genetic diseases resulting from abnormal formation of intracellular vesicles. In HPS, dysfunction of melanosomes results in oculocutaneous albinism, and absence of platelet dense bodies causes a bleeding diathesis. In addition, some HPS patients suffer granulomatous colitis or fatal pulmonary fibrosis, perhaps due to mistrafficking of a subset of lysosomes. The impaired function of specific organelles indicates that the causative genes encode proteins operative in the formation of certain vesicles. Four such genes, HPS1, ADTB3A, HPS3, and HPS4, are associated with the four known subtypes of HPS, i.e. HPS-1, HPS-2, HPS-3, and HPS-4. ADTB3A codes for the β3A subunit of adaptor complex-3, known to assist in vesicle formation from the trans-Golgi network or late endosome. However, the functions of the HPS1, HPS3, and HPS4 gene products remain unknown. These three genes arose with the evolution of mammals and have no homologs in yeast, reflecting their specialized function. In contrast, all four known HPS-causing genes have homologs in mice, a species with 14 different models of HPS, i.e. hypopigmentation and a platelet storage pool deficiency. Pursuit of the mechanism of mammalian vesicle formation and trafficking, impaired in HPS, relies upon investigation of these mouse models as well as studies of protein complexes involved in yeast vacuole formation.


Abbreviations
HPS

Hermansky–Pudlak syndrome

MRP

mannose-6-phosphate receptor

CPY

carboxypeptidase Y

ALP

alkaline phosphatase

PVC

prevacuolar compartment

MVB

multiple vesicular body

EEA1

Early endosome antigen 1

BLOC-1

Biogenesis of lysosome-related organelles complex 1

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Individual cellular functions rely upon specific, suitable environments provided by specialized compartments called vesicles. Knowledge of the formation and maintenance of vesicular compartments remains incomplete, but enormous advances have been made in recent years. Some of our new insights arose from investigations of yeast, flies, mice and men whose systems for vesicle formation and trafficking have gone awry. In humans, many of these disorders are called, collectively, Hermansky–Pudlak syndrome (1) or HPS. In this review, we describe the roles that the causative genes and their respective proteins have played in studies of the genesis of intracellular organelles.

The specific organelles affected in HPS are the melanosome, the platelet dense body, and the lysosome, which all share certain integral membrane proteins. For example, the melanosome ME491, a melanoma-associated antigen expressed strongly during the early stages of tumor progression, corresponds to the dense body CD63 or granulophysin, which is the same as the lysosome Lysosomal Integral Membrane Protein-1 (LIMP-1) or Lysosomal Associated Membrane Protein-3 (LAMP-3) (2). In HPS, dysfunction of each organelle results in particular aspects of the disorder (3–8).

Impairment of melanosome formation causes different degrees of albinism. Early in development, this leads to improper migration of neural crest cells and abnormal decussation of the optic nerve fibers. Dysfunction of retinal pigment epithelial cells, which among a host of other functions provide nutritional support to rods and cones, may contribute to visual impairment. Visual acuity varies from 20 of 50 to 20 of 400 in HPS (5, 9, 10), and is largely uncorrectable by refractive lenses. Patients nearly always have congenital horizontal nystagmus, and strabismus is common (9, 10). On examination, the irides transilluminate and the fundi exhibit scattered hypopigmentation. Hair color ranges from dark brown to completely white, and skin pigment also varies widely (11). Sun exposure predisposes to actinic keratoses and skin cancer, including basal cell carcinoma, squamous cell carcinoma, and melanoma. Sun avoidance and the use of sunscreen are important therapeutic maneuvers in this regard.

The absence of platelet dense bodies, which are detectable on whole mount electron microscopy (12), leads to a condition known as storage pool deficiency. Dense bodies contain calcium (which confers the electron density), polyphosphates, serotonin, adenosine triphosphate, and adenosine diphosphate (ADP). When stimulated, the dense granules release their contents, and ADP triggers aggregation of neighboring platelets. This secondary aggregation response, which can be measured in a clinical laboratory, is impaired in HPS. Affected individuals have varying degrees of soft tissue and mucus membrane bleeding (5). Bruises generally appear at first ambulation, cuts bleed longer than expected, and epistaxis is common, especially before adolescence. Wisdom tooth removal and childbirth often bring the bleeding diathesis to recognition. Treatment involves local use of thrombin and gelfoam, prophylactic use of 1-desamino-8-d-arginine vasopressin and, in serious cases, platelet transfusions.

Lysosomal involvement in HPS probably has several pathologic consequences. On a cellular level, some HPS patients accumulate ceroid lipofuscin, an amorphous lipid–protein complex, and this appears to be stored within lysosomes (13). It accumulates within the kidney, bone marrow, spleen, liver, large intestine and sloughed urinary epithelial cells. In addition, a subset of HPS patients develop pulmonary fibrosis (14–16) and/or granulomatous colitis (5, 17, 18). As these involve cells that lack melanosomes and dense bodies, lysosomal abnormalities are considered responsible. The pulmonary fibrosis generally manifests in the fourth or fifth decades of life and leads to death within 10 yr. The granulomatous colitis of HPS presents, on average, at 16 yr of age (5) and resembles Crohn's colitis in symptoms and response to therapy.

The specialized cell, tissue, and organ systems of Homo sapiens manifest specific signs and symptoms caused by vesicular abnormalities. Some of the proteins aberrant in humans with HPS may have progenitors in other, more primitive species. We now trace the progression of vesicle-forming systems from yeast to Drosophila to mouse and man.

Yeast

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Yeast genetics, studied largely in Saccharomyces cerevisiae, has made the greatest impact on our knowledge of the molecular mechanisms involved in targeting of proteins to lysosomes. The yeast vesicle corresponding to the mammalian lysosome is the acidic vacuole, which plays a central role in yeast physiology. The vacuole influences pH and osmoregulation, protein degradation, and storage of amino acids, small ions, and polyphosphates. Molecular machineries and biosynthetic pathways involved in the formation of the yeast vacuole and mammalian lysosome are remarkably conserved (19–21). Many newly synthesized proteins reach the vacuole after being diverted at the late Golgi complex to endosomal compartments (22).

Genetic screens have identified a large number of yeast mutants that are blocked at various points along this pathway. Some mutants mislocalize yeast vacuolar proteins (vps, for vacuolar protein sorting deficient) (23–26), and others exhibit decreased vacuolar protease activity (pep, for peptidase deficient) (27). Genetic, biochemical and cell biological studies on these mutants have provided molecular insights into the various pathways for delivering proteins to the yeast vacuole.

The biosynthetic sorting of proteins from the late Golgi complex to the yeast vacuole involves transport along two distinct routes the ‘carboxypeptidase Y’ (CPY) pathway and the ‘alkaline phosphatase’ (ALP) pathway (Fig. 1). Most vacuolar proteins travel through the CPY pathway, from the late Golgi through a prevacuolar compartment (PVC) to the vacuole (25, 28). This pathway resembles mannose-6-phosphate receptor (MPR)-mediated sorting in mammalian cells (19, 21). The ALP pathway sorts proteins from the Golgi complex directly to the vacuole, without passage through a prevacuolar compartment (25, 28).

image

Figure 1. Simplified model of lysosomal biogenesis. (A) Yeast vacuolar and Drosophila pigment granule biogenesis pathways. Proteins known to regulate specific steps in yeast transport are listed in white boxes. The list is not complete. The CPY pathway (upper arrows) transports vacuolar proteins in yeast from the Golgi through the PVC or MVB toward the vacuole. The ALP pathway (lower) carries vacuolar proteins directly to the vacuole, independent of the PVC. Transport of proteins toward the Drosophila pigment granule is blocked in several mutants, indicated in green boxes. (B) Mammalian lysosome and lysosome-related organelle biogenesis pathways. Mouse mutants (pink boxes) and human mutants (yellow boxes) are indicated at their predicted site of action in specific transport steps.

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The CPY pathway

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Carboxypeptidase Y, a soluble hydrolase within the vacuolar lumen, serves as a prototype for the CPY pathway (Fig. 1A). This pathway requires the functional products of more than 100 genes. Mutations in any of these genes result in missorting of proteins to the cell surface by a default pathway and, in some cases, abnormal vacuolar morphology (25, 26).

The CPY pathway can be divided into four stages. The first stage involves protein sorting into membranes/vesicles at the late Golgi, and transport of these vesicles toward the PVC. Proteins functioning in this stage include clathrin, the adaptor complex 1 (AP-1), vps10p (the CPY receptor), Peptidase deficient-1 (PEP1) (identical to vps10), drs2 (a P-type adenosine triphosphatase), and all ‘Class D’vps proteins, such as vps1p (a dynamin homolog), vps15p (homologous to the Ser/Thr family of protein kinases), vps34p (a PI3-kinase homolog), vps8p (which interacts with vps21p), vps21p [a rab/ypt small guanosine triphosphatase (GTPase)], vps9p (a guanine nucleotide exchange factor), and vps45p (a Sec1p family member regulating certain (target membrane)-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (t-SNARES)) (25, 26, 29, 30).

The second stage of the CPY pathway consists of formation and maturation of the PVC, which is identical to the mammalian multiple vesicular body (MVB). Mutants of all ‘Class E’vps proteins, including vps4p, vps27p, vps28p, result in PVCs having a multilamellar structure. This membrane accumulation appears to result from a block in membrane trafficking out of the PVC, both forward to the vacuole and backward to the Golgi apparatus (30–32).

The third stage involves recycling, or transport from the PVC to the Golgi. This process requires the vps52p/ vps53p/vps54p complex (33), and the ‘retromer’ complex consisting of two subcomplexes: vps26p/vps29p/vps35p and vps5p/vps17p (34). All three complexes are conserved in higher eukaryotes, suggesting an important role in endosome–Golgi retrieval.

The final stage in the CPY pathway consists of membrane transport from the PVC to the vacuole. Proteins functioning in this process are the ‘Class B’ and ‘Class C’vps proteins. ‘Class B’vps mutants (e.g. vps3p, vps5p, vps26p) show fragmented vacuoles, so this class of proteins probably functions in late vacuole formation (30). ‘Class C’vps proteins (vps11p, vps16p, vps18p and vps33p) interact with each other and are localized at the vacuolar membrane. ‘Class C’vps mutants also show fragmented vacuoles, so the proteins may be part of a complex functioning in the final step of membrane transport to the vacuole (35). The ‘Class C’ vps complex might also operate at other stages of the vacuolar transport pathway (36).

The ALP pathway

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Alkaline phosphatase, a membrane-bound hydrolase, serves as a prototypic protein for the ALP pathway (Fig. 1A). Alkaline phosphatase transport to the vacuole does not involve a prevacuolar compartment (37), and persists unaltered in cells that are blocked in specific parts of the CPY pathway. In fact, ALP leaves the Golgi complex via vesicles having a different membrane composition than that of CPY-containing vesicles (37, 38). Adaptor complex-3 (AP-3) is involved in the ALP pathway, although its precise site of action remains unclear (37, 39, 40). The syntaxin-like SNARE, vam3p, is known to follow the ALP pathway to the vacuole (37, 41). The vps41 and vps39p mutants are blocked in the processing of ALP, have nearly normal CPY delivery, and accumulate structures that resemble mammalian MVB (38, 42).

The CPY and ALP pathways converge at the step involving fusion with the vacuole. The two pathways share gene products affecting vacuole targeting and fusion. In addition, vam3p, the t-SNARE of the vacuole, functions in both protein transport pathways to the vacuole (30, 41). Along with other proteins, vamp3p interacts with ‘Class C’vps gene products (35). Two other proteins whose mutations have effects on both the ALP and CPY pathways are the dynamin homolog vps1 (43) and the rab7 homolog ypt7 (44).

Drosophila melanogaster

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

By the time evolution produced flies, specialized pigment cells had developed to assist in vision. These cells, typified by those in the eye of D. melanogaster, contain membrane-bound organelles called pigment granules. Each pigment granule is filled with either ommochrome (brown) pigment, or drosopterin (red) pigment; the latter gives the Drosophila eye its red color (45). More than 80 mutations affecting eye color in D. melanogaster have been described (45, 46). Some of the eye color genes encode pigment-synthesis enzymes (necessary for ommochrome or drosopterin production) or ATP-binding cassette transporter (ABC) membrane transporters required for transport of pigment precursors. In contrast, the ‘granule group’ of mutant genes encodes proteins that function in the delivery of proteins to pigment granules (45–47). These mutants have a reduction in both types of pigment, as well as additional phenotypes unrelated to eye color. Some of the granule group genes are homologous to genes whose protein products are required for lysosomal biogenesis in other species. This became apparent when the δ subunit of AP-3 was found to cause the garnet phenotype (48, 49). Mammalian and yeast AP-3 complexes were already recognized to mediate protein transport to lysosomal organelles (39, 50, 51). Later, deficiencies of the μ, β and σ subunits of AP-3 were found to correspond to the granule group mutants carmine, orange and ruby, respectively (52, 53), further supporting the concept that Drosophila pigment granules, like yeast vacuoles, are related to lysosomes.

Gene defects have been established in three other members of the granule group. The vps41, vps33 and vps18 genes are mutated in light, carnation and deep orange, respectively (54–56). The vps18p and vps33p genes are part of a multisubunit complex that also contains vps11p and vps16p (35). A mutation in any of these subunits in yeast results in accumulation of prevacuolar multivesicular bodies (35), similar to the accumulation of multivesicular bodies found in pigment cells of the Drosophila mutant deep orange (56) (Fig. 1A).

The vps41p mutants in yeast also accumulate structures that resemble mammalian MVB (38). This could be because vps41p indirectly interacts with, and may function in the same pathway with, the vps11p/vps16p/vps18p/vps33p complex. Vps41p interacts with vps39p (57), vps39 yeast mutants show multivesiculated prevacuolar structures (42), and vps39p can bind to the vps11 subunit of the vps11p/vps16p/vps18p/vps33p complex (57). In addition, in yeast and in humans, vps41p interacts with the δ subunit of AP-3 and is required for formation of AP-3 coated carrier vesicles (58, 59).

Identification of the gene defects in the granule group mutants claret, lightoid, pink, and purploid may reveal other critical components of the pigment granule/lysosome biogenesis pathway.

Mus Musculus

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

If Drosophila brought pigmented granules to the evolutionary chain, mice contributed a group of specialized intracellular vesicles. In general, the responsible genes have no homologs in more primitive species, and their mutations result in phenotypes resembling human HPS. In fact, 14 genetically distinct mice display a combination of defects in melanosomes (hypopigmenation), platelet dense bodies (prolonged bleeding times), and in most cases, lysosomes (urinary excretion of lysosomal enzymes) (60). The defective organelles are of lysosomal lineage, and the defects are comparable with vacuolar transport defects in yeast and pigment granule defects in Drosophila. Each mouse model exhibits autosomal recessive inheritance, and the severity of the organelle defects varies among mutants (Table 1). The specific phenotypic features of each mouse model may help predict the site of action of the encoding protein as well as interactions among proteins (Table 1 and Fig. 1B).

Table 1.  Genes associated with pigment dilution due to abnormal vesicle formation or trafficking
 HumanMouseDrosophilaYeast
Gene nameGene productMutantbGene productMutantGene productMutantGene productMutant pathwaya
  • a

    CPY, defect in carboxypeptidase Y pathway; ALP, defect in alkaline phosphatase pathway; ?, unknown.

  • b  

    GS, Griscelli syndrome; ES, Elejalde syndrome; CHS, Chediak–Higashi syndrome.

HPS1HPS1HPS-1MEP-1 (ep)pale earCG12855
ADTB3AAP3B1HPS-2Ap3b1pearlCG11427 (rb)rubyAPL6ALP
HPS3HPS3HPS-3HPS3cocoaCG14562
HPS4HPS4HPS-4HPS4light earCG4866
PallidinPLDNPldnpallid
MutedMUTEDmutedmuted
RGGTARABGGTARabggtagunmetalCG12007
δ-3AP3D1 (δ)Ap3d1 (δ)mochaCG11197 (δ)garnetAPL5ALP
μ-3AP3M1(μ3A)Ap3m1(μ3 A)CG3035 (μ3)carmineAPM3ALP
σ-3AP3S1 (σ3A)Ap3s1 (σ3A)CG3029 (σ3)orangeAPS3ALP
VPS33VPS33AVPS33CG12230 (car)carnationVPS33CPY
VPS41VPS41VPS41CG18028(lt)lightVPS41ALP
VPS18VPS18VPS18CG3093 (dor)deep orangeVPS18CPY
RAB27ARAB27AGSRab27AashenGM10914(Ypt)??
Myosin 5AMYO5AESMYO5AdiluteMyosin VMyo2??
MelanophillinMLPHMlphleaden
LYSTLYSTCHSLYSTbeigedAKAP550 dCG9011 – – BPH1?

Pale ear/light ear

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The gene responsible for the pale ear mouse (ep) was found by homology to the first human HPS gene, itself identified by positional cloning (61–63). The HPS1 gene product has no known function and has no homology to any other known protein. The pale ear mouse has a phenotype identical to that of another mutant, light ear (le), whose gene was recently identified as HPS4 (64). The HPS4 gene product also has no known function and no homology to any known protein. Both ep and le mutants have similar coat colors, both show a unique hypopigmentation of ears, tail and feet (60, 65), and both manifest fewer and enlarged melanin granules in different cell types (62, 66, 67). In addition, le/le; ep/ep doubly homozygous mice have a phenotype identical to that of the two singly homozygous mutants (68); this suggests that the proteins function in the same pathway.

No direct interaction between the HPS1 and HPS4 gene products has been shown, but studies in transfected melanoma cells demonstrated partial colocalization in vesicular structures in the perinuclear area (64). In addition, tissues of the le mouse show no HPS1 protein expression (64), again suggesting that the HPS1 and HPS4 proteins function in the same pathway and could possibly interact. In human melanotic cells, the HPS1 protein resides in uncoated vesicles and early stage melanosomes. It exists in two distinct high-molecular weight complexes (a ∼200 kDa cytosolic and a >500 kDa membrane-bound complex) distributed among uncoated vesicles, early stage melanosomes and the cytosol (69). Identification of the other components of these complexes will reveal more about the function and site of action of the HPS1 protein, as well as its possible interaction with the HPS4 protein.

Pallid/muted/reduced pigment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The pallid (pa) mouse shows hypopigmentation, prolonged bleeding time, elevation of kidney lysosomal enzymes, deficiency of serum α1-antitrypsin activity, and abnormal otolith formation (60, 70, 71). Long-term survival is reduced compared with that of wild-type mice, due mainly to lung lesions consisting of air space enlargement and destruction of alveolar septa (70, 72). The pa mouse has reduced or absent melanosomes, and the remaining melanosomes exist in early developmental stages (types I and II melanosomes), as assessed by 3,4-dihydroxyphenylalanine (DOPA) reactivity (71, 73). In choroid cells, melanosomes appear aggregated in large membrane-bound granules (73).

The pa mouse is defective in the pallidin (Pldn) gene (74), which encodes pallidin, a small coiled-coil protein with no homologs in mouse, Drosophila or yeast. Yeast two-hybrid experiments showed interaction of pallidin with syntaxin 13 (Stx13), a t-SNARE protein that mediates vesicle fusion and docking (74). Stx13 interacts with early endosome antigen 1 (EEA 1), an effector of Rab5 GTPase that helps tether early endosomes prior to fusion (75). The STX13/Pldn complex may function as a premelanosomal t-SNARE assisting fusion of specific vesicles that traffic from the trans-Golgi to the premelanosome, carrying the melanosomal proteins tyrosinase, Tyrp 1 and Tyrp 2 (76, 77).

Recent reports indicate that pallidin is a component of an ∼200 kDa asymmetric protein complex named BLOC-1 for biogenesis of lysosome-related organelles complex-1 (78). Although the molecular mass of BLOC-1 resembles that of an HPS1 protein complex (69), coimmunoprecipitation experiments failed to detect an association between pallidin and HPS1, suggesting that the HPS1 complex is distinct from BLOC-1 (78). The lack of pallidin in muted (mu) and reduced pigment (rp) fibroblasts suggests that the mu and rp gene products might encode components of BLOC-1 that are required for pallidin stability (78).

The muted gene, mutated in the muted mouse, codes for a small coiled-coil protein (like pallidin), which has no homologs in yeast or Drosophila. Muted is distributed in a vesicular pattern throughout the cell body and dendrites (79). The number and size of melanosomes in the muted mouse is decreased and the remaining melanosomes often contain unusual inclusions and lamellar bodies (79). The mu mouse has balance defects caused by the absence of inner ear otoliths (60, 79). The muted protein is present in drastically reduced concentrations in pallid and rp mouse fibroblasts (78), and coimmunoprecipitation experiments show an interaction between pallidin and the muted protein, again suggesting that the muted protein is a part of the BLOC-1 complex (78).

The rp gene has not yet been identified. The rp mouse has a phenotype similar to that of pa and mu in its coat hypopigmentation and prolonged bleeding time. rp, along with the gunmetal mouse (see below), displays cutaneous rather than oculocutaneous albinism; eye pigment formation is normal (60).

Biogenesis of lysosome-related organelles complex-1 function appears independent of AP-3 activity, and no physical interaction between BLOC-1 and AP-3 is demonstrable by coimmunoprecipitation. The phenotype of the mu/pe double mutant is significantly more severe than that of each single mutant, and pa and mu fibroblasts do not have enhanced plasma membrane trafficking of LAMP proteins, as shown for mocha. A clue to the function of BLOC-1 might come from the interaction of pallidin with syntaxin-13, which would indicate a role in membrane fusion. Pallidin can associate with actin filaments (78), which are abundant not only in the plasma membrane area, but also in the region of the Golgi complex (80, 81).

Pearl/mocha

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Two mouse coat color mutants, mocha (mh) and pearl (pe), were found to carry mutations encoding the δ and β3A subunits of AP-3, respectively (82, 83), further emphasizing the connection of AP-3 to the biogenesis of lysosome-related organelles. Both mh and pe mice exhibit coat and eye color dilution (because of fewer and smaller melanosomes in pigment forming cells), prolonged bleeding times, and decreased secretion of lysosomal enzymes (60). The mocha mice also exhibit balance problems due to otolith defects which eventually lead to deafness (84), as well as neurologic defects such as hyperactivity and seizures (82, 85).

Unlike mocha, pearl does not show neurologic abnormalities, and pearl has normal hearing and balance. This could be explained by normal expression in pearl of brain-specific β3B. This isoform of β3A, also known as β-NAP, allows for normal AP-3 function in the pearl brain (82, 86). The pearl mutant is unique among the mouse coat color mutants in that it displays night blindness, i.e. a reduced visual sensitivity to dim light, possibly because of the lower density of melanosomes in the retina (60, 87).

Ruby eye, ruby eye-2, cocoa

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The mouse models ruby eye (ru), ruby eye-2 (ru-2) and cocoa (coa) have the same distinct coat color, different from all other mouse models (60). This might mean that these three genes function as a complex or in the same vesicular processing step. While the ru and ru-2 genes await isolation, the coa mouse gene has been identified as HPS3 (88).

The ru gene has reduced numbers of melanocytes in the retina, skin, and other melanized tissues, and the melanosomes are spheroidal rather than ovoid (60); this suggests that the ru gene product functions in a relatively late step of vesicle formation such as MVB formation (Fig. 1B) [MBVs are intermediates in the endosomal pathway; they have a limiting membrane inside of which small membrane vesicles reside (77)]. Mast cells of the ruby eye mouse exhibit a threefold increase in the number and duration of transient fusion events. This implicates a function for ru in regulating closure of the cell fusion pores which connect the lumen of a secretory vesicle with the extracellular environment during exocytosis (89).

The coa mouse has a mild phenotype with normal lysosomal enzyme secretion by platelets and kidney cells. The coa gene has a high density of small, abnormally shaped, unmelanized early melanosomes and few mature melanosomes, with disorganized and granular matrices. The coa eye has a paucity of melanosomes in both the retinal pigment epithelium and the choroid, which also contains excessive multilamellar bodies and aberrant melanosomes. These features, together with localization of HPS3 throughout the cytoplasm (88), suggest a function late in melanosome biogenesis.

Gunmetal

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The gunmetal (gm) mouse is unusual among the HPS models in that it exhibits only cutaneous albinism, not oculocutaneous albinism (90). The gm mouse also exhibits thrombocytopenia, with approximately one-third the normal number of platelets (91), and abnormal α granules which contain striated inclusions and decreased contents of fibrinogen, platelet factor 4, and von Willebrand factor. Excess levels of von Willebrand factor are found in plasma of the gm mouse, suggesting a defect in trafficking/processing rather then defective synthesis (90). The gm platelets are increased in size, and dense granule contents are decreased to approximately 50% of normal; the bleeding time is still significantly increased (Table 2) (60, 91). These features make gm resemble α/δ storage pool deficiency (92) rather than classical HPS. The gm gene, RGGTA, codes for rab geranylgeranyl transferase α, an enzyme that attaches geranylgeranyl groups to small GTPases (i.e. rabs) (93) for insertion into membranes (94). The rab proteins play key roles in membrane remodeling and trafficking (95).

Table 2.  Murine mutants with pigment dilution and storage pool deficiency
Mouse modelMouse chromosome/ positionGene defectBleeding timeaLysosomal dysfunctionbCoat colorOtolith formation defectMelanosome (number and shape)Comments
  1. a   Normal bleeding time in mouse (C57BL/6J strain) is 2.1 min (60). b Excretion of lysosomal enzymes (60). ?, unreported.

Cappuccino (cno)5/?Unknown>15 min+UniqueFewer, mostly  early stage 
Cocoa (coa)3/12.5 cMHPS3>15 minSimilar to ru,  ru-2Small, abnormal  shapeHuman HPS-3  disease
Gunmetal (gm)14/20.7 cMRABGGTA>15 minUnique?No eye hypopigmentation
Light ear (le)5/60.0 cMHPS4>15 min+Similar to epMostly early stage,  normal shapeHuman HPS-4 disease
Mocha (mh)10/43.0 cMAP3D1>15 min+Unique+Fewer and smaller,  normal shapeImbalance, hyperactivity
Muted (mu)13/21.0 cMmuted>15 min+Unique+Fewer, irregular shapeImbalance
Pale ear (ep)19/42.0 cMHPS1>15 min+Similar to leMostly early stage,  normal shapeHuman HPS-1 disease
Pallid (pa)2/67.6 cMpallidin>15 min+Unique+Fewer, early stage,  normal shape 
Pearl (pe)13/47.0 cMADTB3A>15 min+UniqueFewer and smaller,  normal shapeHuman HPS-2 disease
Reduced pigment (rp)7/2.0 cMUnknown>15 min+Unique?No eye hypopigmentation
Ruby eye (ru)19/44.0 cMUnknown>15 min+Similar to ru-2Fewer, spheroidal shape 
Ruby eye-2 (ru2)7/25.0 cMUnknown>15 min+Similar to ru,  coa? 
Sandy (sdy)13/23.0 cMUnknown>15 min+Unique? 
Subtle gray (sut)3/16.4 cMUnknown7.5 minUnique? 

Subtle gray, sandy, cappuccino

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The subtle gray (sut) mouse has an intermediate bleeding time and mild pigment dilution. In sut, platelet dense granule serotonin is reduced, but adenine nucleotide concentrations are normal (60, 96). Lysosomal enzyme secretion is also normal. The sut gene product may act in specialized vesicle trafficking rather than in vesicle formation, as lysosomal function is normal (Table 1) (60), and most platelet contents are present. Mild coat hypopigmentation also points to a melanosomal transport defect. The sut locus, although situated on mouse chromosome 3 syntenic to human chromosome 3q24 (where HPS3 resides) is not the murine counterpart of human HPS3 (97).

The sandy (sa) mouse has diluted pigment in its eyes and fur, and has a prolonged bleeding time. Platelet serotonin levels are very low and platelet aggregation is impaired (98). Platelet dense granules are reduced in number and lysosomal enzyme secretion is decreased (98). The severity of the phenotype indicates a role for the sa gene product early in melanosome biogenesis.

The cappuccino (cno) mouse has severe coat hypopigmentation, which resembles that of pallid, a prolonged bleeding time, and decreased lysosomal enzyme secretion (60, 99). The cno melanosomes are immature and decreased in number in both the eyes and skin. Behavioral abnormalities, such as head tilting and poor balance, suggest otolith defects in the inner ear (99). The cno gene has not been isolated, but it has been shown that the cno gene product functions in a pathway independent of AP-3 (99).

Homo sapiens; the Hermansky–Pudlak syndromes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

While the mouse displays 14 types of hypopigmentation and platelet storage pool deficiency, man has so far found only four genes in himself that cause a similar constellation of findings (Table 2). More are likely to be discovered, of course. The distribution of patients among the four known subtypes of HPS is skewed by the large number (∼450) of north-west Puerto Rican patients homozygous for a founder mutation in HPS1. These individuals constitute approximately 70% of the world's known cases of HPS. If they are disregarded, the frequency of each HPS subtype can be estimated from the NIH experience involving 52 patients outside of north-west Puerto Rico. In this group, 14 (27%) have HPS-1, three (6%) have HPS-2, 15 (29%) have HPS-3, seven (13%) have HPS-4, and 13 (25%) have no known mutation.

We now describe the four known HPS subtypes on both clinical and cell biologic bases.

Clinical findings

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Clinically, oculocutaneous albinism and platelet storage pool deficiency characterize all types of HPS, but some clinical findings are specific for certain subtypes. For example, HPS-1 and HPS-4 patients can suffer granulomatous colitis and pulmonary fibrosis, while HPS-3 patients can have colitis but have no manifested pulmonary fibrosis to date (Table 3). HPS-2 patients are too few and too young to reveal if they will ever develop these complications (100, 101). Among and within HPS subtypes, the extent of hypopigmentation (Fig. 2), visual acuity deficit and bleeding diathesis varies widely, although HPS-3 appears milder with respect to these signs and symptoms (102). The dermatologic, ophthalmologic, and pulmonary findings of HPS-1 have been extensively described (10, 11, 16); in fact, because of the relatively high prevalence of HPS-1, the clinical characteristics of this subtype have, in the past, defined HPS as a medical entity (103).

Table 3.  Clinical findings in human HPS subtypes a
SubtypeOculocutaneous albinismVisual acuity deficitbBleeding disorderInfectious diathesisPulmonary fibrosisColitis
  • a  

    −, absent; +, mild; ++, moderate; +++, severe; ?, unknown (only three patients). Severity can vary considerably within each subtype.

  • b

    b   Varies from 20 of 50 to 20 of 400.

HPS-1++++++++++++++
HPS-2++++++??
HPS-3++++ – /+++
HPS-4++++++++++++++
image

Figure 2. Skin and hair hypopigmentation in patients with HPS-1 (A), HPS-2 (B), HPS-3 (C), and HPS-4 (D).

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HPS-1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The HPS1 protein shows no homology to any other known proteins and its function is unknown. HPS1 exists as part of two distinct large complexes in melanotic cells, i.e. an ∼200 kDa cytosolic and a >500 kDa membrane-bound complex, distributed among uncoated vesicles, early stage melanosomes and the cytoplasm (69). Patients with HPS-1, who have no expression of the HPS1 gene on Northern blot (61), have melanocytes which are hypopigmented, with severely decreased melanin content (0–50% of normal). In intact HPS-1 melanocytes, tyrosine hydroxylase activity was almost half that of normal, but in cell lysates of HPS-1 melanocytes it was within the normal range (104), indicating a sorting defect rather than a synthesis defect.

Morphologic investigations of HPS-1 melanosomes employed staining with DOPA, which localizes functional tyrosinase. These studies showed numerous premelanosomes lacking DOPA reaction product distributed throughout the cell body and dendrites (104), indicating that tyrosinase sorting requires the HPS1 gene product. In addition, large membranous complexes were detected containing membrane-bound chambers, unpigmented and pigmented melanosomes, irregular deposits of DOPA reaction product, and granular/amorphous material (Fig. 3). DOPA-positive ‘rings’, delineated on either side by limiting membranes, were also detected (104). In normal melanocytes, the intracellular distribution of tyrosinase-related protein-1 (Tyrp1) and granulophysin appeared in a fine granular pattern throughout the cell. In HPS-1 cells, in contrast, these proteins appeared in large granules throughout the cytoplasm, probably representing the membranous structures and/or ring-like structures (104), again indicating a missorting of these additional melanosomal proteins. Missorting of Tyrp1 and tyrosinase was also demonstrated by transfecting normal melanocytes with anti-sense HPS1 cDNA (105). All these findings suggest a function of HPS1 (likely as part of a complex) in sorting and early vesicle (premelanosome) formation from the trans-Golgi network.

image

Figure 3. HPS-1 melanocytes are characterized by membranous complexes. Melanocytes cultured from patients with HPS-1 were processed with (A and C) or without (B) DOPA histochemistry to localize functional tyrosinase. (A) Perinuclear (cell at bottom) and dendritic (cell at top) area of two adjacent melanocytes demonstrating 50-nm DOPA-positive vesicles (arrowheads) around the trans-Golgi network of the perinuclear area (cell at bottom), throughout the cytoplasm of the dendritic area (cell at top) and in the vicinity of a DOPA-positive membranous structure (arrowhead with asterisk). Some melanosomes contained (arrows) or were devoid of (arrows with asterisks) DOPA reaction product (N = nucleus; open arrow = membranous complexes; scale bar = 1.0 μm). (B) High magnification of a membranous complex in the dendritic area of a melanocyte not treated with DOPA histochemistry demonstrating limiting membranes (arrowheads) incompletely surrounding the complex and demarking an apparent cisternal space (asterisk). Within the complex are irregular profiles of limiting membranes (arrows) and two putative early stage melanosomes (stars) (scale bar = 0.35 μm). (C) High magnification of a membranous complex in a melanocyte treated with DOPA histochemistry demonstrating two-unit membranes (arrowheads) delineating a cisterna that can be filled with (arrows) or devoid of (arrow with asterisk) DOPA reaction product, indicating the presence or absence of tyrosinase, respectively. At some sites, the opposing unit membranes appear to coalesce and extrude DOPA reaction product from between them (arrowheads with asterisks) or curve out of the plane of sectioning (brackets). Melanosomes in the vicinity or within the membranous profiles can be filled with (open arrows) or devoid of (open arrows with asterisks) DOPA reaction product. Neighboring 50-nm diameter vesicles can also contain (arrows with black stars) or be devoid of (arrows with white stars) DOPA reaction product (scale bars = 0.2 μm) [images adapted from Boissy et al. (104)].

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HPS-2

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The ADTB3A gene, defective in HPS-2 (106), encodes the β3A subunit of AP-3. Adaptor complexes (AP) are heterotetrameric and are involved in vesicle/membrane formation and trafficking. Adaptor complexes play a role in formation of coated vesicles, as well as in the selection of cargo for these vesicles. Adaptor complex-3, contains δ, μ, and σ subunits in addition to β3A. The β3A subunit is thought to bind clathrin, whose rigid triskelion structure causes outpouching from an existing membrane. In this fashion, AP-3 mediates the formation of vesicles such as the melanosome and platelet dense body.

Clues to the specific role of AP-3 in vesicle formation come from studies of fibroblasts and melanocytes deficient in β3A. In HPS-2 fibroblasts, deficient in AP-3 activity, trafficking of lysosomal proteins (e.g. LAMP-1, LAMP-2, and LAMP-3) through the plasma membrane is enhanced, suggesting that the plasma membrane provides a default pathway which operates when normal AP-3 function is blocked (106). In HPS-2 melanocytes, tyrosinase expression is reduced and limited to multivesicular bodies in the perinuclear region (Fig. 4B). However, expression of Tyrp1 in HPS-2 melanocytes is unaffected (107). These results suggest that trafficking of tyrosinase but not Tyrp1 is mediated via AP-3. Transfection of HPS-2 melanocytes with ADTB3A cDNA restored β3A activity and cured the melanocytes of their tyrosinase mislocalization, confirming that AP-3 functions to traffic tyrosinase to melanosomes (107). This helps explain the hypopigmentation of HPS-2 patients.

image

Figure 4. HPS-2 melanocytes are characterized by late endosome/multivesicular body-like structures. Melanocytes cultured from (A) a control individual or (B and C) patients with HPS-2 were processed for DOPA histochemistry. (A) Multivesicular bodies with minimal (1) or no (2) reaction product were occasionally present in control melanocytes. (B) In contrast, multivesicular bodies with much reaction product (arrows) were abundant in HPS-2 melanocytes. (C) The HPS-2 multivesiculated bodies exhibited finger-like protrusions of their limiting membranes (1) and the DOPA positive reaction product appeared as aggregates (2), and/or within vesicles (3). (scale bars: A and B = 0.4 μm; C = 0.25 μm) [images adapted from Huizing et al. (107)].

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HPS-3

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The function of the HPS3 protein is unknown, and HPS3 has no homology to any known protein. However, HPS3 has a putative clathrin binding domain and potential dileucine sorting signals, whose importance to HPS3 function remains to be determined (108). HPS3 melanocytes do not show obvious ultrastructural abnormalities. However, they do contain some melanosomes with relatively minimal DOPA reaction product as well as numerous 50 nm DOPA-positive vesicles throughout the dendrites (Fig. 5). This is in agreement with the relatively mild phenotype of HPS-3 patients (102) and the cocoa mouse. HPS3 most likely functions in a late step of lysosome/melanosome biogenesis.

image

Figure 5. HPS-3 melanocytes are characterized by extensive distribution of 50-nm diameter, DOPA-positive vesicles. Melanocytes cultured from a patient with HPS-3 were processed for DOPA histochemistry. (A) Golgi area (G) of the cell body demonstrating reaction product in the trans-Golgi network (white arrowheads) and 50-nm vesicles (black arrowheads). Reaction product was absent (arrows with asterisks) or present (arrows) from melanosomes in the vicinity. (N = nucleus; scale bar = 2.5 μm). (B) Dendritic area demonstrating numerous DOPA-positive melanosomes, few relatively DOPA-negative melanosomes (arrows with asterisks), and an abundance of 50-nm diameter, DOPA-positive vesicles (arrowheads) scattered throughout the cytoplasm (N = nucleus; scale bar = 2.5 μm).

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HPS-4

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

There is evidence that the recently identified HPS4 protein, which has no known function and no homology to other proteins, interacts with HPS1 (64). To date, no ultrastructural studies have been performed on HPS-4 melanocytes. Preliminary immunofluorescence data show accumulation of LAMP-1 and LAMP-3 in large aggregates in the perinuclear area in HPS-4 fibroblasts, similar to findings for HPS-1 fibroblasts (M. Huizing, unpublished data). HPS4 might be part of a high molecular weight complex that includes HPS1.

Related disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Several rare genetic disorders of hypopigmentation resemble HPS. Choroideremia patients, with defects in a rab-escort protein, share visual defects with HPS patients (109), and patients with the Gray Platelet syndrome (gene defect unknown) show abnormalities in α granules rather than dense granules (110). Chediak–Higashi syndrome (CHS) is characterized by variable hypopigmentation of skin, hair, and eyes, a bleeding diathesis, progressive neurologic dysfunction, and severe immunologic deficiency (111–113). The CHS cells show giant lysosomes and lysosome-like organelles (114). The CHS melanocytes also contain giant, morphologically normal melanosomes with reduced pigmentation and aberrant trafficking and secretion of tyrosinase (115). The gene defective in CHS is LYST, which encodes a large protein (∼430 kDa) with unknown function localized to the cytoplasm (116). How LYST defects change lysosome morphology/shape is unknown, but alterations in several biochemical pathways (e.g. protein kinase C) have been implicated (113). The beige mouse is the murine counterpart of human CHS (116).

Griscelli syndrome (GS) shows hypopigmentation of the skin, silvery gray hair, immune abnormalities, and hemophagocytic syndrome (117, 118). Another disorder, Elejalde syndrome (ES), is characterized by a similar phenotype, but has neurologic complications and no immunologic defects (119). Griscelli syndrome is caused by mutations in RAB27A, a small guanosine triphosphate-binding protein involved in targeting and fusion of transport vesicles (118, 120). The mouse ashen is the murine counterpart of GS (121). Elejalde syndrome (with the murine counterpart dilute) is caused by mutations in MYO5A, an actin-binding motor protein (120, 122). The three mouse models, leaden[caused by mutations in melanophilin (123)], ashen, and dilute form a unique group with hypopigmented coat color caused by pigment clumping in hair shafts (60). Their gene products, rab27A, myosin 5A, and melanophilin, have been shown to function in melanosome transport down dendrites for capture within the dendritic tips (124).

Molecular biology of HPS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Mutations in all four known human HPS causing genes have been identified (8). Most patients have mutations in HPS1, which has an open reading frame of 2103 bp, is divided into 20 exons, and is located on chromosome 10q23.1–23.3 (61). The first and most common mutation in HPS1 is a 16-bp duplication in exon 15, responsible for HPS in north-west Puerto Rico (61). Thirteen other mutations have been reported (8) and we recently found four new mutations (125).

HPS-2 disease is caused by mutations in ADTB3A (101, 106), which has an open reading frame of 3281 bp, is divided into 27 exons, and has been mapped to chromosome 5q13.2 (101). Four mutations in three patients have been reported (101, 106).

HPS-3 disease is caused by mutations in HPS3 (108), which consists of 17 exons, has a 3015-bp open reading frame, and has been mapped to chromosome 3q24 (108). A founder mutation (3904-bp deletion) has been discovered in central Puerto Rico (108) and a different founder mutation (IVS5 + 1G [RIGHTWARDS ARROW] A) in Ashkenazi Jewish HPS patients. Five other HPS3 mutations have been reported (102).

The HPS4 gene was recently found to cause HPS (64). HPS4 has an open reading frame of 2127 bp, consists of 14 exons, and has been mapped to chromosome 22q11.2–q12.2. Five different mutations have been reported (64).

A significant subset of HPS patients do not have mutations in HPS1, ADTB3A, HPS3 or HPS4.

Protein: complexes and interactions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The progressive sophistication of specialized intracellular vesicles, as evolution proceeds from yeast to man, reflects a series of vertical relationships between the genes of one species and the next (Table 2). In addition, horizontal relationships exist among the proteins responsible for forming vesicles out of extant membranes. In particular, various protein complexes are known to play roles in protein trafficking and vesicle formation. Examples already mentioned include the interactions of the HPS1 and HPS4 proteins, the BLOC-1 complex, and the AP-3 complex. Others, noted below, deserve further investigation.

AP-1, AP-2, AP-4

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Although AP-3 mutations cause one type of HPS (HPS-2), three other APs are known to exist. The AP-1 complex is ubiquitously expressed in mammals, and mutations appear to be lethal (126). Adaptor complex 1 binds clathrin and acts in vesicle formation at the trans-Golgi. Adaptor complex-2 mediates endocytosis from the plasma membrane and is ubiquitously expressed in mammals. Its function in lysosomal biogenesis appears to be minimal. Adaptor complex-4 (127, 128) is not expressed in yeast or Drosophila, so its function may be rather advanced. It is associated with the trans-Golgi network (127, 128), but appears to function on non-clathrin coated vesicles (126–128).

VPS complexes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

The complex of the four ‘Class C’ vps genes, vps11p/ vps16p/vps18p/vps33p, is conserved from yeast to man. Mutations in one of several subunits cause lysosomal biogenesis defects in yeast and Drosophila. We hypothesized that these four genes would be candidates to cause HPS in humans, and we identified the human homologs of the subunits (129). However, we found no mutations in any of these genes in our HPS patients. The vps39p and vps41p mutants also form a complex in yeast (57) and are conserved in evolution. However, we also failed to find mutations in vps41 and vps39 in HPS patients.

Other complexes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Many other known and unknown protein complexes play important roles in specific vesicular transport steps in lysosomal biogenesis. Several recent reviews address the function and interactions of the Rab/YPT family (120), SNAREs (131), syntaxins (132), the cytoskeleton (actin and microtubuli) (133), and membrane lipid composition (134). Understanding these and other processes will help reveal the mechanism of lysosomal biogenesis.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References

Evolution from yeast to higher eukaryotes has introduced different lysosome-related organelles into specialized cells. Examples include melanosomes in melanocytes, dense granules in platelets, lytic granules in T lymphocytes and natural killer cells, basophilic granules in basophils and mast cells, azurophilic granules in neutrophils, and class II major histocompatibility complex glycoproteins (MIICs) in antigen-presenting cells such as macrophages, dendritic epithelial cells and B lymphoblasts. These dedicated vesicles in specialized cells are not necessary in yeast, but are essential for more developed organisms. Hence, genes required for overall cell viability are conserved from yeast through humans, while genes producing specialized organelles of the lysosomal pathway, e.g. ‘HPS genes’, are present only in higher eukaryotes.

How did nature deal with the need to acquire particular genes for the maintenance of specialized organelles? First, some single copy yeast genes could have multiple isoforms in eukaryotes to achieve diversification of function. Examples are yeast vps33, which has mammalian vps33a and vps33b isoforms (129) and the tissue specific isoforms β3A and β3B of AP-3 (86). Secondly, some yeast orthologues could change their domain organization in higher eukaryotes as a result of adaptation during evolution. For example, human vps41 has two alternative splice forms; one is membrane-associated and contains a C-terminal RING-H2 sequence motif, while the other splice form lacks this motif and is primarily cytoplasmic (59). Thirdly, lysosome biogenesis in higher eukaryotes could rely upon novel genes having no homologs in yeast. This appears to be the case for the HPS1, HPS3, HPS4, pallidin, and muted genes.

Of course, lysosome-related organelles, such as the melanosome and platelet dense granule, coexist with conventional lysosomes in the same cell (77). Furthermore, the intracellular vesicles we regard as lysosomes really consist of many distinct functional groups. One of these is the secretory lysosome, which shares several characteristics with melanosomes and platelet dense granules (135). All three have a single limiting membrane, share common integral membrane proteins by virtue of a common Golgi origin, and undergo secretion. All these attributes, which differentiate them from other intracellular compartments, require sorting mechanisms to ensure proper targeting of components to each organelle.

The genes that achieve this specialized protein and membrane sorting and targeting are, in general, HPS genes. HPS1, HPS3, and HPS4 are not evolutionarily conserved and have no homologs in yeast, although ADTB3A, responsible for HPS-2, does. Even in this case, however, the specialized nature of vesicle formation is evident. The yeast AP-3 complex mediates transport of alkaline phosphatase to the vacuole but does not contribute to the trafficking of vps10p, the receptor of the vacuolar CPY. Similarly, mammalian AP-3 mediates lysosomal targeting of LAMP-1, LAMP-2, and LIMP-2 or CD63, but is not involved in MPR transport. In the melanocyte, it appears that AP-3 mediates tyrosinase targeting to the melanosome, but is not involved in Tyrp1 transport (107).

Some clues to the stage at which HPS genes operate arise from the phenotypes of HPS model mice (60). In these animals, abnormal urinary secretion has been found for lysosomal but not for non-lysosomal enzymes. This points to a late, post-Golgi (i.e. post-early sorting vesicle formation) stage of granule biogenesis or secretion, rather than to earlier stages at which lysosomal and non-lysosomal enzymes are not yet sorted. In addition, Swank et al. (84) tested proton pump activity, necessary to maintain an acidic pH in lysosome-like organelles. No abnormalities in acidification were noted in HPS mouse mutants, absolving this process as a cause of vesicular dysfunction. We have studied HPS-1, HPS-3, and HPS-4 fibroblasts with the fluorescent probe LysoTracker Red (Molecular Probes, Eugene, OR, USA), which quantifies acidity, and also found no defects in lysosomal pH (M. Huizing, unpublished data).

Although protein deficiencies are likely responsible for most aberrations in vesicular trafficking, some attention should be paid to defects of phospholipid membrane composition (134). Fusion pores, critical for membrane fusion events, are closed by virtue of slight changes in the lipid composition of the pore (136), and post-Golgi sorting events are likely mediated by phosphoinositides (137). Hence, altered phospholipid levels may result in improper vesicle formation or trafficking.

Future investigations into HPS-causing genes will draw from basic genetic and cell biologic principles. For example, mice can be bred to be doubly homozygous for two HPS-causing genes. If the double mutant shows a phenotype similar to that of the homozygous single mutants, it is likely that their gene products interact and/or act in the same pathway. If the double mutant phenotype is more severe than that of the single homozygous mutants, then the gene products likely function in separate pathways. In addition, examining the morphology of an HPS patient's melanocytes at the electron microscope level may indicate the location of the protein defect. Some illustrative findings might include MVB formation, fragmented vacuoles, or accumulation of small vesicles.

It took millions of years for yeast to rise to the level of man, and for pigment vesicles to be bred into specialized cells. Yet the secrets of intracellular organelle formation are likely to be revealed within a single human lifetime. The process has begun.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Yeast
  5. The CPY pathway
  6. The ALP pathway
  7. Drosophila melanogaster
  8. Mus Musculus
  9. Pale ear/light ear
  10. Pallid/muted/reduced pigment
  11. Pearl/mocha
  12. Ruby eye, ruby eye-2, cocoa
  13. Gunmetal
  14. Subtle gray, sandy, cappuccino
  15. Homo sapiens; the Hermansky–Pudlak syndromes
  16. Clinical findings
  17. Cell biology
  18. HPS-1
  19. HPS-2
  20. HPS-3
  21. HPS-4
  22. Related disorders
  23. Molecular biology of HPS
  24. Protein: complexes and interactions
  25. AP-1, AP-2, AP-4
  26. VPS complexes
  27. Other complexes
  28. Discussion
  29. References
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