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Hermansky-Pudlak Syndrome

Written By

Naoki Oiso and Akira Kawada

Submitted: 14 September 2012 Published: 06 February 2013

DOI: 10.5772/53573

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1. Introduction

Oculocutaneous albinism is classified into non-syndromic oculocutaneous albinism (OCA) and syndromic OCA including Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome (CHS) and Griscelli syndrome (GS). Both non-syndromic and syndromic OCAs are autosomal recessive disorders. Human HPS is genetically divided into nine forms, HPS type 1 (HPS-1) to HPS-9. Human HPS can be sub-classified into four subgroups which are associated with protein complexes encoded by the causative genes. In this session, we summarize (1) the clinical features of HPS, (2) the mice and rat models of HPS, and (3) the molecular functions.


2. The clinical features of HPS

In 1959, Hermansky and Pudklak described two cases of OCA associated with hemorrhagic diathesis.1 Currently, the condition is known as HPS. HPS is a rare heterogeneous autosomal recessive syndrome which is typically characterized by OCA, bleeding diathesis, and lysosomal ceroid storage resulting from defects of multiple cytoplasmic organelles: melanosomes, platelet dense core granules, and lysosomes.2 The storage of ceroid-like material in lysosomes induces restrictive lung disease, ulcerative colitis, kidney failure, and cardiomyopathy.

Accumulation of mice models, identification of causative genes and functional analysis indicated that HPS could be sub-classified into four groups according to four protein complexes, biogenesis of lysosome-related organelles complex-3 (BLOC-3) (HPS-1 and HPS-4), adaptor protein-3 (AP-3) (HPS-2), BLOC-2 (HPS-3, HPS-5 and HPS-6) and BLOC-1( HPS-7, HPS-8 and HPS-9).3-5 Currently, more than 16 mice strains and more than 2 rat strains are known as models of human HPS (Table 1). HPS-1 is caused by mutation in HPS1,6 HPS-2 is caused by mutation in AP3B1,7 HPS-3 is caused by mutation in HPS3,8 HPS-4 is caused by mutation in HPS4,9 HPS-5 is caused by mutation in HPS5,10 HPS-6 is caused by mutation in HPS6,10 HPS-7 is caused by mutation in DTNBP1,11 HPS-8 is caused by mutation in BLOC1S3,12 and HPS-9 is caused by mutation in PLDN.13 Functional analyses identify that most of all HPS proteins construct complexes, BLOC-1, BLOC-2, BLOC-3, AP3, class C vacuolar protein sorting (VPS), and Rab geranylgeranyl transferase (RABGGT).

Mouse modelsHuman typeGenesProtein complexes
pale earHPS-1HPS1BLOC-3
pearl HPS-2AP3B1AP3
cocoa HPS-3HPS3BLOC-2
light earHPS-4HPS4BLOC-3
reduced pigmentationHPS-8BLOC1S3BLOC-1
buff?VPS33Aclass C VPS
subtle gray?SLC7A11
Rat models
Fawn-Hooded rat?RAB38
Tester-Moriyama rat?RAB38

Table 1.

Animal models, human types, causative genes and their protein complexes in HPS.

HPS-1 and HPS-4, the group of BLOC-3, are the most dominant and typical subtypes. The founder effect in HPS-1 is present in the region of northwest Puerto Rico.8 HPS-1 and HPS-4 are characterized by OCA by deficiency of melanosomes, bleeding by loss of platelet dense core granules, and systemic organ involvement (restrictive lung disease, granulomatous colitis, kidney failure, and cardiomyopathy) by the storage of lysosomal ceroid-like substances due to impaired lysosomes. The clinical features of OCA and bleeding diathesis are present in infancy. Bleeding tendency is important to diagnose.

HPS-2, the group of AP3, is the most severe and rare subtype, with 15 cases reported in the literature.14 Clinical manifestations include OCA, a platelet storage pool defect, interstitial lung disease, and recurrent bacterial and viral infections due to immunodeficiency.14 Patients with HPS-2 exhibit neutropenia that is responsive to granulocyte colony-stimulation factor, deficiency of natural killer and natural killer T-cells, T-lymphocyte dysfunction, and in one case hemophagocytic lymphohistiocytosis.14

HPS-3, HPS-5, and HPS-6, the group of BLOC-2, are the milder and relatively rare subtypes. The founder effect in HPS-3 is present in the area of central Puerto Rico.8 HPS-3, HPS-5 and HPS-6 are relatively milder forms of the disease in that both OCA and bleeding diathesis are mild and pulmonary fibrosis and granulomatous colitis generally does not develop.10, 15-17

HPS-7, HPS-8, and HPS-9, the group of BLOC-1, are extremely rare subtypes. HPS-7 is only found in a 48-year-old Portuguese woman with OCA, a bleeding tendency, mild shortness of breath on exertion and reduced lung compliance but otherwise normal pulmonary function.11 HPS-8 is found in a Pakistani family12 and an Iranian patient.18 HPS-8 is characterized by typical OCA and a bleeding diathesis. Pulmonary fibrosis, granulomatous colitis, or neutropenia are not detected in the cases. 12, 18 HPS-9 is only found in a 9-month-old male of Indian ancestry.13 The patient showed OCA with generalized hypopigmentation, nystagmus, iris transillumination, and retinal hypopigmentation; respiratory distress requiring a 3 week admission to a neonatal intensive-care unit for respiratory support; and platelet electron microscopy showing absent platelet delta granules.13

Recombinant factor VIIa (rFVIIa) is useful for dangerous bleeding such as refractory menorrhagia.19 Progressive HPS-1 pulmonary fibrosis is effectively treated by pirfenidone, a small molecule that inhibits TGF-beta-mediated fibroblast proliferation and collagen synthesis in vitro.20 Infliximab is effective for granulomatous colitis in HPS patients.21 The efficacy of infliximab suggests that TNF-α plays a pivotal role in the pathogenesis.21


3. The mice and rat models of HPS

Mice models of HPS can be grouped into BLOC-3 (pale ear22, 23 and light ear9), BLOC-2 (cocoa24, ruby-eye-210 and ruby-eye10), BLOC-1 (sandy11, reduced pigmentation25, pallid26, cappuccino27 and muted28), AP-3 (pearl29 and mocha30), class C VPS (buff31), RABGGT (gunmetal32), and others (misty33 and subtle gray34) (Table 1). Two rat models of HPS, Fawn-Hooded Rat and Tester-Moriyama Rat, are genetically identical with no expression of RAB38.35

Gautam et al. contacted mutant mice doubly or triply deficient in protein subunits of the various BLOC complexes and/or the AP-3 adaptor complex and tested for viability and for abnormalities of lysosome-related organelles (LROs) including melanosomes, lamellar bodies of lung type II cells and platelet dense granules.36 They showed that double and triple mutant HPS mice provide unique and practical experimental advantages in the study of LROs.36 Long-Evans Cinnamon rats with a point mutation in the initiation codon of Rab38 small GTPase are investigated for the pathogenesis of interstitial pneumonia via aberrant lung surfactant secretion.37 Thus, mice and rat models are indispensable for recognizing the molecular function in LROs and the pathogenesis of HPS.


4. The molecular functions

The complexes involving in the pathogenesis of HPS are BLOC-3, BLOC-2, BLOC-1, AP-3 adaptor complex, and class C VPS. BLOC-3 is composed of HPS1/pale ear and HPS4/light ear.38-40 BLOC-2 conprises HPS3/cocoa, HPS5/ruby-eye-2 and HPS6/ruby-eye.10, 41 BLOC-1 is constructed by proteins of HPS7/DTNBP1/sandy, HPS8/BLOC1S3/reduced pigmentation/ BLOS3, cappuccino, muted, pallid, BLOS1, BLOS2 and snapin.42, 43 AP-3 (subunits δ/mocha, β3/HPS2/ AP3B1/pearl, μ3, σ3) is one of the family of heterotetrameric clathrin adaptors.44 The class C VPS is composed of VPS11, VPS16, VPS18, and VPS33/buff.45

Figure 1.

BLOC-1, -2, -3, AP-3 and class C VPS complexes involve in membrane trafficking from endosomes to lysosomes and lysosome-related organelles, melanosomes and dense core granules in platelets.

Adaptor protein complexes are composed of heterotetramers (two large subunits, a medium-sized subunit and a small subunit) and sort cargo into vesicles for transport from one membrane compartment of the cell to another.46 AP-3 traffics cargo from tubular endosomes to late endosomes, lysosomes, and related organelles via the bound to BLOC-1, vimentin, clathrin and others.46, 47

The class C VPS core complex (VPS33A/B, VPS11, VPS16 and VPS18) is essential for late endosome and lysosome assembly and for numerous endolysosomal trafficking pathways.48 Two class C VPC complexes, homotypic fusion and protein sorting (HOPS) and class C core vacuole/endosome tethering (CORVET), incorporate diverse biochemical functions: they tether membranes, stimulate Rab nucleotide exchange, guide SNARE assembly to drive membrane fusion, and possibly act as ubiquitin ligases.48

BLOC-1 functions in selective cargo exit from early endosomes toward lysosomes and lysosome-related organelles such as melanosomes and BLOC-2 act sequentially in the same pathway.49 Melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2.49 BLOC-3 is constructed by HPS1 and HPS4 heterodimers.50 BLOC-3 interacts with the GTP-bound form of the endosomal GTPase, Rab9. BLOC-3 might function as a Rab9 effector in the biogenesis of lysosome-related organelles.50


5. Conclusion

Now, HPS is a representative disorder of aberrant membrane trafficking. HPS genes have been identified with mice models. The function of encoded proteins has been accompanied with cell biology in yeast, worm, fly and animal models. Membrane trafficking is crucial for cells to survive and play their active functions. Further emerging investigation will reveal more precise pathogenesis in HPS.


biogenesis of lysosome related organelle complex (BLOC)-1, -2, -3

adaptor protein complex 3 (AP3)

vacuolar protein sorting (VPS)

Rab geranylgeranyl transferase (RABGGT)

homotypic fusion and protein sorting (HOPS)

class C core vacuole/endosome tethering (CORVET)


  1. 1. HermanskyFPudlakPAlbinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with histochemical studies.Blood1959141629
  2. 2. OhJHoLAla-melloSet alMutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity.Am J Hum Genet 199862593598
  3. 3. LiWRusiniakM. EChintalaSet alMurine Hermansky-Pudlak syndrome genes: regulators of lysosome-related organelles.Bioessays 20042661628
  4. 4. Di Pietro SMDell’Angelica EC. The cell biology of Hermansky-Pudlak syndrome: recent advancesTraffic2005652533
  5. 5. HuizingMHelip-wooleyAWestbroekWet alDisorders of lysosome-related organelle biogenesis: clinical and molecular genetics.Annu Rev Genomics Hum Genet 2008935986
  6. 6. OhJBailinTFukaiKFengG. Het alco-first author). Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet 1996143006
  7. 7. Dell’Angelica ECShotelersuk V, Aguilar RC, et al. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor.Mol Cell 199931121
  8. 8. AniksterYHuizingMWhiteJet alMutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.Nat Genet 20012837680
  9. 9. SuzukiTLiWZhangQet alHermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.Nat Genet 2002303214
  10. 10. ZhangQZhaoBLiWOisoNet alco-first author). Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nat Genet 20033314553
  11. 11. LiWZhangQOisoNet alco-first author). Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet 200335849
  12. 12. MorganN. VPashaSJohnsonC. Aet alA germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8)Am J Hum Genet 2006781606
  13. 13. CullinaneA. RCurryJ. ACarmona-riveraCet alA BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9.Am J Hum Genet 20118877887
  14. 14. GochuicoB. RHuizingMGolasG. Aet alInterstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex diseaseMol Med 2012185664
  15. 15. HuizingMAniksterYFitzpatrickD. Let alHermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiencyAm J Hum Genet 200169102232
  16. 16. HuizingMHessRDorwardHet alCellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5. Traffic2004571122
  17. 17. HuizingMPedersonBHessR. Aet alClinical and cellular characterisation of Hermansky-Pudlak syndrome type 6J Med Genet 20094680310
  18. 18. CullinaneA. RCurryJ. AGolasGet alA BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak Syndrome type 8Pigment Cell Melanoma Res 20122558491
  19. 19. LohseJGehrischSTauerJ. Tet alTherapy refractory menorrhagia as first manifestation of Hermansky-Pudlak syndrome.Hamostaseologie 2011Suppl 1: S613
  20. 20. OBrienKTroendleJGochuicoBR, et al. Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis.Mol Genet Metab 201110312834
  21. 21. GrucelaA. LPatelPGoldsteinEet alGranulomatous enterocolitis associated with Hermansky-Pudlak syndromeAm J Gastroenterol 200610120905
  22. 22. GardnerJ. MWildenbergS. CKeiperN. Met alThe mouse pale ear (ep) mutation is the homologue of human Hermansky-Pudlak syndrome.Proc Natl Acad Sci U S A 199794923843
  23. 23. FengG. HBailinTOhJet alMouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare’AT-AC’ intron.Hum Mol Genet 199767937
  24. 24. SuzukiTLiWZhangQet alco-first author). The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky-Pudlak syndrome-3 gene. Genomics 200178307
  25. 25. GwynnBMartinaJ. ABonifacinoJ. Set alReduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex.Blood200410431819
  26. 26. HuangLKuoY. MGitschierJet alThe pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency.Nat Genet 19992332932
  27. 27. CicciotteS. CGwynnBMoriyakaKet alCappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1). Blood 200310144027
  28. 28. ZhangQLiWNovakE. Ket alco-first author). The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking. Hum Mol Genet 200211697706
  29. 29. FengLSeymourA. BJiangSet alco-first author). The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky-Pudlak syndrome and night blindness. Hum Mol Genet 1999832330
  30. 30. KanthetiPQiaoXDiazM. Eet alMutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles.Neuron19982111122
  31. 31. SuzukiTOisoNGautamRet alco-first author). The mouse organellar biogenesis mutant buff results from a mutation in Vps33a, a homologue of yeast vps33 and Drosophila carnation. Proc Natl Acad Sci U S A 2003100114650
  32. 32. DetterJ. CZhangQMulesE. Het alRab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.Proc Natl Acad Sci U S A 20009741449
  33. 33. BlasiusA. LBrandlKCrozatKet alMice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological functionProc Natl Acad Sci U S A 2009106270611
  34. 34. ChintalaSLiWLamoreuxM. Let alSlc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cellsProc Natl Acad Sci USA 2005102109649
  35. 35. OisoNRiddleS. RSerikawaTet alThe rat Ruby (R) locus is Rab38: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain.Mamm Genome 20041530714
  36. 36. GautamRNovakE. KTanJet alInteraction of Hermansky-Pudlak Syndrome genes in the regulation of lysosome-related organellesTraffic2006777992
  37. 37. OsanaiKHiguchiJOikawaRet alAltered lung surfactant system in a Rab38deficient rat model of Hermansky-Pudlak syndromeAm J Physiol Lung Cell Mol Physiol 2010L243-51.
  38. 38. ChiangP. WOisoNGautamRet alThe Hermansky-Pudlak syndrome 1 (HPS1) and HPS4 proteins are components of two complexes, BLOC-3 and BLOC-4, involved in the biogenesis of lysosome-related organelles.J Biol Chem 2003278203327
  39. 39. MartinaJ. AMoriyamaKBonifacinoJ. SBLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4.J Biol Chem 20032782937684
  40. 40. NazarianRFalcon-perezJ. MDell’angelica EC. Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4.Proc Natl Acad Sci U S A 200310087705
  41. 41. GautamRChintalaSLiWet alThe Hermansky-Pudlak syndrome 3 (cocoa) protein is a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2).J Biol Chem 20042791293542
  42. 42. Falcon-perezJ. MStarcevicMGautamRet alBLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules.J Biol Chem 2002277281919
  43. 43. StarcevicMDell’angelica EC. Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1).J Biol Chem 200427928393401
  44. 44. SimpsonFBrightN. AWestM. Aet alA novel adaptor-related protein complex.J Cell Biol 199613374960
  45. 45. SatoT. KRehlingPPetersonM. Ret alClass C Vps protein complex regulates vacuolar SNARE pairing and is required for vesicle docking/fusionMol Cell 2000666171
  46. 46. HirstJBarlowL. DFranciscoG. Cet alThe fifth adaptor protein complex.PLoS Biol 2011e1001170 EOF
  47. 47. Newell-litwaKSeongEBurmeisterMet alNeuronal and non-neuronal functions of the AP-3 sorting machinery.J Cell Sci 200712053141
  48. 48. NickersonD. PBrettC. LMerzA. JVps-C complexes: gatekeepers of endolysosomal traffic.Curr Opin Cell Biol 20092154351
  49. 49. SettyS. RTenzaDTruschelS. Tet alBLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles.Mol Biol Cell 20071876880
  50. 50. KloerD. PRojasRIvanVet alAssembly of the biogenesis of lysosome-related organelles complex-3 (BLOC-3) and its interaction with Rab9J Biol Chem 20102857794804

Written By

Naoki Oiso and Akira Kawada

Submitted: 14 September 2012 Published: 06 February 2013