Molecular Genetics of Hermansky–Pudlak Syndrome

Andrew R Cullinane, National Institutes of Health, Bethesda, Maryland, USA
Marjan Huizing, National Institutes of Health, Bethesda, Maryland, USA
William A Gahl, National Institutes of Health, Bethesda, Maryland, USA

Published online: February 2013

DOI: 10.1002/9780470015902.a0024328

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive, genetically heterogeneous disorder characterised by oculocutaneous albinism and a bleeding diathesis. Subtype specific features such as neutropenic immunodeficiency and fatal lung fibrosis also occur. To date, nine human HPS subtypes (HPS-1 to HPS-9) and their associated genes have been identified. All of the HPS protein products are involved in biogenesis of lysosome-related organelles (LROs) in specialised cells, including melanosomes in melanocytes and delta granules in platelets. The HPS proteins are all components of one of three biogenesis of lysosome-related organelles complexes (BLOC-1, BLOC-2 or BLOC-3) or the adaptor protein complex-3. These complexes are essential for the correct formation of LROs, which are produced by the complex interaction of proteins, membranes and vesicles from the endocytic and biosynthetic pathways. Cells from patients with LRO disorders serve as useful tools for elucidating the complex pathways involved in the biogenesis of these organelles.

Key Concepts:

  • HPS is caused by mutations in nine known genes and is characterised by oculocutaneous albinism and a bleeding tendency.
  • The proteins that are encoded by the HPS genes are all required for the correct formation of lysosome-related organelles (LROs).
  • LROs share features with lysosomes but have distinct morphology, composition and/or functions.
  • LROs are maintained by the regulated flow of proteins, membranes and vesicles among the complex endosomal machinery.
  • Novel players of LRO biogenesis are revealed by human disease and animal mutations, which continue to provide invaluable resources for elucidating the complex pathways involved in the biogenesis of these organelles.

Keywords: Hermansky–Pudlak syndrome; HPS; lysosome-related organelles; albinism; bleeding; neutropenia; lung fibrosis; melanocytes; platelet delta granules; biogenesis of organelles

Figure 1. Clinical aspects of Hermansky–Pudlak syndrome. Subtypes of HPS are grouped according to the protein complex to which their subtype belongs (BLOC-3, AP-3, BLOC-2 and BLOC-1). The associated genes and proteins are indicated with each subtype. Control images are on the left. BLOC-3 defective patients (HPS-1 and HPS-4) have the most severe albinism of the skin, hair and eyes, whereas in AP-3 and BLOC-2 defective patients the albinism is variable, but generally milder. BLOC-1 defective patients tend to develop pigment over time. HPS patients’ lack of iris pigmentation results in iris transillumination; a phenomenon in which light shone through the pupil is transmitted back through the iris. All HPS patients have absence of delta granules (electron dense) in their platelets (red arrows in control) assessed by whole-mount electron microscopy. Packed melanocytes grown from a skin biopsy show variably reduced pigment in the HPS patients compared to control. A negative correlation between the amount of pigment in the packed melanocyte pellet and the severity of albinism can clearly be seen. Platelet EM pictures are from White J (University of Minnesota). Huizing et al. (2004), Cullinane et al. (2012) reproduced by permission of J Wiley and Sons. Huizing et al. (2009) reproduced by permission of BMJ Group. Huizing et al. (2001), Cullinane et al. (2011) by permission of Elsevier.
Figure 2. High-resolution CT scans of control and HPS-1 lungs. The HPS-1 patient's lungs clearly show fibrosis (white scar tissue), bullae (air-filled blisters) and loss of alveoli. This image is representative of all HPS patients that have lung fibrosis (HPS-1, HPS-4 and HPS-2). Images are courtesy of Gochuico B (NHGRI, NIH).
Figure 3. The endosomal system and LRO biogenesis. The endosomal system is a collection of highly dynamic compartments defined by their morphology and function. Instead of focusing on a specific cell type, this schematic diagram shows the basic endosomal elements involved in generic LRO biogenesis. Solid arrows depict maturation or biogenesis of a compartment whereas dashed arrows represent the movement of cargo. The early (sorting) endosome is the major sorting centre of the cell, where Golgi-derived biosynthetic cargo and endocytosed proteins are sorted toward LROs or late endosomes and in turn lysosomes. Proteins can also be recycled back to the plasma membrane or Golgi. Specialised LROs coexist with nonspecialised lysosomes in the same cell, and contents destined for each compartment must be sorted separately and appropriately. In some LRO-containing cells, LRO formation involves sequential delivery of LRO-specific proteins. The mature LRO acquires specific accessory proteins (Rabs, motor proteins and SNAREs) that assist in its function and/or localisation. Image produced by Pan J (NHGRI, NIH).
Figure 4. Schematic diagrams of the biogenesis of lysosome-related organelles complexes (BLOCs) and the AP-3 complex. The proteins identified as components of each BLOC and the AP-3 complex and their interactions within each complex are indicated. Most of the BLOC subunits are associated with subtypes of Hermansky–Pudlak syndrome. BLOC-1 consists of BLOS1, BLOS2, BLOS3 (HPS-8), Cappuccino, Dysbindin (HPS-7), Muted, Pallidin (HPS-9) and Snapin. BLOC-2 consists of HPS3 (HPS-3), HPS5 (HPS-5) and HPS6 (HPS-6) and BLOC-3 has HPS1 (HPS-1) and HPS4 (HPS-4). The AP-3 complex consists of one of each of four subunits (, , and ), where the gene encoding the subunit is mutated in HPS-2.
Figure 5. Schematic diagram of the functions of the BLOCs and AP-3 complexes in melanosome biogenesis in melanocytes. The stage I or premelanosome acquires PMEL-17 directly from the Golgi and matures to a stage II melanosome with the polymerisation of PMEL-17, allowing for subsequent melanin deposition. At this stage, the melanosomes have characteristic stripes. Stage II melanosomes mature into stage III melanosomes by acquiring other melanogenic proteins such as TYRP1 and tyrosinase from the early or sorting endosome. This ultimately results in melanin-laden stage IV melanosomes required for pigmentation. Identifying the trafficking defects of tyrosinase and TYRP1 proteins in HPS patients’ melanocytes revealed the functions of the BLOCs and AP-3 complex. BLOC-3 proteins work very early in this process, by aiding the delivery of both tyrosinase and TYRP1 from the Golgi to the sorting endosome. The AP-3 complex assists in the delivery of both proteins from the sorting endosome to the maturing melanosome, whereas BLOC-1 and BLOC-2 ensure correct delivery of only TYRP1 at the same trafficking step. Image produced by Pan J (NHGRI, NIH).
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Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
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Article Title: Molecular Genetics of Hermansky–Pudlak Syndrome
 
How to Cite close
Cullinane, Andrew R, Huizing, Marjan, and Gahl, William A(Feb 2013) Molecular Genetics of Hermansky–Pudlak Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024328]