Hermansky-Pudlak syndrome

Summary

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder affecting lysosome-related organelles (LRO), including dense platelet granules. HPS causes oculo- cutaneous hypopigmentation, bleeding diathesis and granulomatous colitis or pulmonary fibrosis. To date, there is no curative treatment and the clinical management depends on the severity of symptoms. A prompt diagnosis of HPS patients could improve their quality of life and clinical management. However, the absence of a specific platelet function test, the wide molecular heterogeneity, and the lack of phenotypegenotype correlations hamper the rapid diagnosis. Nine subtypes of HPS have been identified as a result of mutations in nine genes that codify for proteins involved in formation and shuttle of the LRO. The molecular characterization of patients and knowledge derived from animal models of HPS contribute to the understanding of biogenesis and function of the LRO.

This paper describes a patient with a novel homozygous nonsense mutation causing HPS and provides a review of the literature focusing on recent advances in the molecular characterization and physiopathology of HPS.

Zusammenfassung

Das Hermansky-Pudlak-Syndrom (HPS) ist eine seltene, autosomal-rezessive Krankheit, die Lysosom-relevante Organellen (LRO) und insbesondere elektronendichte Granula beeinträchtigt. HPS verursacht okulokutane Hypo -pigmentierung, hämorrhagische Diathese und granulomatöse Kolitis sowie Lungen -fibrose. Zurzeit existiert keine kurative Therapie, die klinische Behandlung hängt vom Schweregrad der Symptome ab. Eine frühzeitige Diagnose von HPS-Patienten könnte die Lebensqualität und klinische Behandlung verbessern. Das Fehlen eines spezifischen Thrombozytenfunktionstests, die breite molekulare Heterogenität und die fehlende Phäno typ-Genotyp-Korrelation erschweren jedoch eine schnelle Diagnostik. Neun HPS-Subtypen wurden als Folge von Mutationen in neun Genen identifiziert, die Proteine kodieren, welche bei der Bildung und Ausscheidung der LRO beteiligt sind. Die molekulare Charakterisierung von Patienten und das aus HPS-Tiermodellen erlangte Wissen tragen zum weiteren Verständnis der Biogenese und Funktion der LRO bei.

Diese Arbeit beschreibt einen Patienten mit neuartiger homozygoter, HPS-verursachender Nonsense-Mutation und bietet einen Literaturüberblick mit Schwerpunkt auf jüngste Fortschritte in der molekularen Charakterisierung und Pathophysiologie des HPS.

Keywords

Hermansky-Pudlak syndrome - inherited platelet disorders - dense granules

Schlüsselwörter

Hermansky-Pudlak-Syndrom - erbliche Blut -gerinnungsstörung - dichte Granula

• References

• 1 Bolton-Maggs PH, Chalmers EA, Collins PW. et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006; 135: 603-633.
• 2 Salles II, Feys HB, Iserbyt BF, De Meyer SF. et al. Inherited traits affecting platelet function. Blood Rev 2008; 22: 155-172.
• 3 Nurden AT, Nurden P. Congenital platelet disorders and understanding of platelet function. Br J Haematol 2014; 165: 165-178.
• 4 Thon JN, Italiano JE. Platelets: production, morphology and ultrastructure. Handb Exp Pharmacol 2012; 3-22.
• 5 Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with histochemical studies. Blood 1959; 14: 162-169.
• 6 Dotta L, Parolini S, Prandini A. et al. Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism. Orphanet J Rare Dis 2013; 08: 168.
• 7 Gunay-Aygun M, Huizing M, Gahl WA. Molecular defects that affect platelet dense granules. Semin Thromb Hemost 2004; 30: 537-547.
• 8 Carmona-Rivera C, Golas G, Hess RA. et al. Clinical, molecular, and cellular features of non-Puerto Rican Hermansky-Pudlak syndrome patients of Hispanic descent. J Invest Dermatol 2011; 131: 2394-2400.
• 9 Masliah-Planchon J, Darnige L, Bellucci S. Molecular determinants of platelet delta storage pool deficiencies: an update. Br J Haematol 2013; 160: 5-11.
• 10 Del Pozo AIPozo, Jimenez-Yuste V, Villar A. et al. Successful thyroidectomy in a patient with Hermansky-Pudlak syndrome treated with recombinant activated factor VII and platelet concentrates. Blood Coagul Fibrinolysis 2002; 13: 551-553.
• 11 Gonzalez-Conejero R, Rivera J, Escolar G, Zuazu-Jausoro I, Vicente V, Corral J. Molecular, ultrastructural and functional characterization of a Spanish family with Hermansky-Pudlak syndrome: role of insC974 in platelet function and clinical relevance. Br J Haematol 2003; 123: 132-138.
• 12 Huizing M, Helip-Wooley A, Westbroek W. et al. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet 2008; 09: 359-386.
• 13 Wei AH, Li W. Hermansky-Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis. Pigment Cell Melanoma Res 2013; 26: 176-192.
• 14 Cullinane AR, Curry JA, Carmona-Rivera C. et al. A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9. Am J Hum Genet 2011; 88: 778-787.
• 15 Badolato R, Prandini A, Caracciolo S. et al. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome. Blood 2012; 119: 3185-3187.
• 16 Morgan NV, Pasha S, Johnson CA. et al. A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8). Am J Hum Genet 2006; 78: 160-166.
• 17 Cullinane AR, Curry JA, Golas G. et al. A BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak Syndrome type 8. Pigment Cell Melanoma Res 2012; 25: 584-591.
• 18 Li W, Zhang Q, Oiso N. et al. Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosomerelated organelles complex 1 (BLOC-1). Nat Genet 2003; 35: 84-89.
• 19 Lowe GC, Sanchez IGuiu, Chapman O. et al. Microsatellite markers as a rapid approach for autozygosity mapping in Hermansky-Pudlak syndrome: Identification of the second HPS7 mutation in a patient presenting late in life. Thromb Haemost 2013; 109: 4.
• 20 Anikster Y, Huizing M, White J. et al. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nat Genet 2001; 28: 376-380.
• 21 Huizing M, Anikster Y, Fitzpatrick DL. et al. Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. Am J Hum Genet 2001; 69: 1022-1032.
• 22 Boissy RE, Richmond B, Huizing M. et al. Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrometype 3. Am J Pathol 2005; 166: 231-240.
• 23 Thielen N, Huizing M, Krabbe JG. et al. Hermansky-Pudlak syndrome: the importance of molecular subtyping. J Thromb Haemost 2010; 08: 1643-1645.
• 24 Zhang Q, Zhao B, Li W. et al. Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nat Genet 2003; 33: 145-153.
• 25 Huizing M, Hess R, Dorward H. et al. Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5. Traffic 2004; 05: 711-722.
• 26 Korswagen LA, Huizing M, Simsek S. et al. A novel mutation in a Turkish patient with Hermansky-Pudlak syndrome type 5. Eur J Haematol 2008; 80: 356-360.
• 27 Schreyer-Shafir N, Huizing M, Anikster Y. et al. A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics. Hum Mutat 2006; 27: 1158.
• 28 Huizing M, Pederson B, Hess RA. et al. Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6. J Med Genet 2009; 46: 803-810.
• 29 Carmona-Rivera C, Simeonov DR, Cardillo ND. et al. A divalent interaction between HPS1 and HPS4 is required for the formation of the biogenesis of lysosome-related organelle complex-3 (BLOC-3). Biochim Biophys Acta 2013; 1833: 468-478.
• 30 Oh J, Bailin T, Fukai K. et al. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet 1996; 14: 300-306.
• 31 Oh J, Ho L, Ala-Mello S. et al. Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity. Am J Hum Genet 1998; 62: 593-598.
• 32 Shotelersuk V, Hazelwood S, Larson D. et al. Three new mutations in a gene causing Hermansky-Pudlak syndrome: clinical correlations. Mol Genet Metab 1998; 64: 99-107.
• 33 Spritz RA, Oh J. HPS gene mutations in Hermansky-Pudlak syndrome. Am J Hum Genet 1999; 64: 658.
• 34 Hermos CR, Huizing M, Kaiser-Kupfer MI, Gahl WA. Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases. Hum Mutat 2002; 20: 482.
• 35 Suzuki T, Ito S, Inagaki K. et al. Investigation on the IVS5 +5G --> a splice site mutation of HPS1 gene found in Japanese patients with Hermansky-Pudlak syndrome. J Dermatol Sci 2004; 36: 106-108.
• 36 Natsuga K, Akiyama M, Shimizu T. et al. Ultrastructural features of trafficking defects are pronounced in melanocytic nevus in Hermansky-Pudlak syndrome type 1. J Invest Dermatol 2005; 125: 154-158.
• 37 Iwakawa J, Matsuyama W, Watanabe M. et al. Hermansky-Pudlak syndrome with a novel mutation. Intern Med 2005; 44: 733-738.
• 38 Ito S, Suzuki T, Inagaki K. et al. High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein. J Invest Dermatol 2005; 125: 715-720.
• 39 Merideth MA, Vincent LM, Sparks SE. et al. Hermansky-Pudlak syndrome in two African-American brothers. Am J Med Genet A 2009; 149A: 987-992.
• 40 Vincent LM, Adams D, Hess RA. et al. Hermansky-Pudlak syndrome type 1 in patients of Indian descent. Mol Genet Metab 2009; 97: 227-233.
• 41 Wei A, Lian S, Wang L, Li W. The first case report of a Chinese Hermansky-Pudlak syndrome patient with a novel mutation on HPS1 gene. J Dermatol Sci 2009; 56: 130-132.
• 42 Sandrock K, Zieger B. Current strategies in diagnosis of inherited storage pool defects. Transfus Med Hemother 2010; 37: 248-258.
• 43 Sandrock K, Bartsch I, Rombach N. et al. Compound heterozygous mutations in 2 siblings with Hermansky-Pudlak syndrome type 1 (HPS1). Klin Pädiatr 2010; 222: 168-174.
• 44 Wei A, Yang X, Lian S, Li W. Implementation of an optimized strategy for genetic testing of the Chinese patients with oculocutaneous albinism. J Dermatol Sci 2011; 62: 124-127.
• 45 Carmona-Rivera C, Hess RA, O’Brien K. et al. Novel mutations in the HPS1 gene among Puerto Rican patients. Clin Genet 2011; 79: 561-567.
• 46 Suzuki T, Li W, Zhang Q, Karim A. et al. Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene. Nat Genet 2002; 30: 321-324.
• 47 Anderson PD, Huizing M, Claassen DA et al.. Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Hum Genet 2003; 113: 10-17.
• 48 Bachli EB, Brack T, Eppler E. et al. Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis. Am J Med Genet A 2004; 127A: 201-207.
• 49 Jones ML, Murden SL, Bem D. et al. Rapid genetic diagnosis of heritable platelet function disorders with next-generation sequencing: proof-of-principle with Hermansky-Pudlak syndrome. J Thromb Haemost 2012; 10: 306-309.
• 50 Araki Y, Ishii Y, Abe Y. et al. Hermansky-Pudlak syndrome type 4 with a novel mutation. J Dermatol 2014; 41: 186-187.
• 51 Dell’Angelica EC. AP-3-dependent trafficking and disease: the first decade. Curr Opin Cell Biol 2009; 21: 552-559.
• 52 Dell’Angelica EC, Shotelersuk 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 1999; 03: 11-21.
• 53 Huizing M, Scher CD, Strovel E. et al. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res 2002; 51: 150-158.
• 54 Clark RH, Stinchcombe JC, Day A. et al. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003; 04: 1111-1120.
• 55 Fontana S, Parolini S, Vermi W. et al. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-4864.
• 56 Enders A, Zieger B, Schwarz K. et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood 2006; 108: 81-87.
• 57 Wenham M, Grieve S, Cummins M. et al. Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1. Haematologica 2010; 95: 333-337.
• 58 Kurnik K, Bartsch I, Maul-Pavicic A. et al. Novel mutation in Hermansky-Pudlak syndrome type 2 with mild immunological phenotype. Platelets 2013; 24: 538-543.
• 59 Li W, Rusiniak ME, Chintala S. et al. Murine Hermansky-Pudlak syndrome genes: regulators of lysosome-related organelles. Bioessays 2004; 26: 616-628.
• 60 Hayward CP, Harrison P, Cattaneo M. et al. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 04: 312-319.
• 61 Favaloro EJ. Utility of the PFA-100 for assessing bleeding disorders and monitoring therapy: a review of analytical variables, benefits and limitations. Haemophilia 2001; 07: 170-179.
• 62 Seward Jr SL, Gahl WA. Hermansky-Pudlak syndrome: health care throughout life. Pediatrics 2013; 132: 153-160.
• 63 Harrison P, Lordkipanidze M. Testing platelet function. Hematol Oncol Clin North Am 2013; 27: 411-441.
• 64 White JG. Electron-dense chains and clusters in platelets from patients with storage pool-deficiency disorders. J Thromb Haemost 2003; 01: 74-79.
• 65 Seligsohn U. Treatment of inherited platelet disorders. Haemophilia 2012; 18 (Suppl. 04) 161-165.