What is the pathophysiology of Hermansky-Pudlak syndrome (HPS)?

Updated: Dec 13, 2019
  • Author: Jaclyn Scholtz, MD; Chief Editor: Dirk M Elston, MD  more...
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Hermansky-Pudlak syndrome results from the abnormal formation of intracellular vesicles. The impaired function of specific organelles indicates that the causative genes encode proteins operative in the formation of lysosomes and vesicles. Four such genes, HPS1, ADTB3A, HPS3, and HPS4, are associated with the 4 known subtypes of Hermansky-Pudlak syndrome: Hermansky-Pudlak syndrome type 1 (HPS-1), Hermansky-Pudlak syndrome type 2 (HPS-2), Hermansky-Pudlak syndrome type 3 (HPS-3), and Hermansky-Pudlak syndrome type 4 (HPS-4).

The HPS1 gene is located on band 10q23. The most common mutation in HPS-1 is the most common mutation in Puerto Ricans. In this variant, a 16–base pair frame shift duplication occurs at exon 15 of the HPS1 gene. In the Swiss variant, a frame shift occurs at codon 322 of the HPS1 gene. The gene products of HPS1 remain to be defined.

HPS-2 is caused by a mutation in the gene encoding the beta-3A subunit of the heterotetrameric AP3 complex (ADTB3A), which resides on chromosome 5. ADTB3A is known to assist in vesicle formation from the trans-Golgi network or late endosome.

Because the expression of the beta-3A subunit is normally ubiquitous, deficiency of the beta-3A subunit leads to a precise phenotype in cells with a large number of intracellular granules (eg, neutrophils, natural killer cells, cytotoxic T lymphocytes, platelets, melanocytes). [3] The absence of AP-3 results in a low intracellular content of neutrophil elastase, with the consequence of neutropenia. Abnormal movement of lytic granules and reduced perforin content in cytotoxic T lymphocytes and natural killer cells define their respective defects in cytolytic activity. [3]

Less pronounced severity of immunodeficiency can be due to a novel 2 bp-deletion (c.3222_3223delTG) in the final exon of AP3B1, causing a frameshift and thus a prolonged altered HPS2 protein. The place of the deletion is at the very C-terminal's end, preventing a complete loss of the HPS2 protein. [4]

The HPS3 gene is located on band 3q24. HPS3 is a biogenesis of the lysosome-related organelles complex (BLOC)–2 component. [5]

HPS4 is located at band 22q11.2–q12.2. Similar to HPS1, HPS4 involves the BLOC-3 protein complex.

Hermansky-Pudlak syndrome type 5 (HPS-5) results from a deficiency of the HPS5 protein, a component of BLOC-2. [6] Cells deficient in the HPS5 protein maintain early-stage melanosome formation and Pmel-17 trafficking. [6] However, tyrosinase and TYRP1 are mistrafficked and thus fail to be efficiently delivered to melanosomes of HPS-5 melanocytes. [6] Falcon-Perez et al [7] found that the Drosophila ortholog of the HPS5 subunit of BLOC-2 identically mirrors the granule group gene pink (p) that was first investigated in 1910 but had not been identified at the molecular level. The phenotype of pink mutants was worsened by alterations in AP-3 subunits or in the orthologs of VPS33A and Rab38.

The Hermansky-Pudlak HPS1/pale ear gene regulates epidermal and dermal melanocyte development. [8]

The HPS6 gene (ruby-eye protein) has recently been cloned and linked to Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of BLOC-1. Studies in mutant mice show it expresses no dysbindin protein, owing to a deletion in the gene DTNBP1 (encoding dysbindin); this mutation of the human ortholog DTNBP1 causes the novel form HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex in both muscle and nonmuscle cells. Dysbindin is a component of BLOC-1, which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted, and cappuccino, which are associated with Hermansky-Pudlak syndrome in mice. [9]

A germline mutation in BLOC1S3/ reduces pigmentation and results in a novel variation of Hermansky-Pudlak syndrome, type 8 (HPS-8). [10]

Studies have revealed that many Hermansky-Pudlak syndrome gene products are stable components of at least 3 distinct, ubiquitously expressed protein complexes, named BLOC-1, BLOC-2, BLOC-3, and BLOC-4. Hermansky-Pudlak syndrome–associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; BLOC-1, consisting of 4 Hermansky-Pudlak syndrome proteins (pallidin, muted, cappuccino, HPS-7/sandy); BLOC-2, consisting of HPS-6/ruby-eye, HPS-5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS-1/pale ear and HPS-4/light ear. In the cytosol, HPS-1 (but not HPS-4) is part of yet another complex, termed BLOC-5.

In some investigations, rab geranylgeranyl transferase plays a role in Hermansky-Pudlak syndrome.

Systemic manifestations of Hermansky-Pudlak syndrome involve accumulation of a ceroidlike substance in tissue lysosomes. Ceroid is the name given to the waxlike substance. This lysosomal defect has been reported in reticuloendothelial cells, bone marrow, and lung macrophages. In Hermansky-Pudlak syndrome, particularly the cases in Puerto Rico, ceroid-lipofuscin–like pigment accumulates in lysosomal structures, causing tissue damage, and, upon kidney involvement, this leads to increased urinary dolichol excretion. In addition, clinical evidence of storage disease manifesting with restrictive lung disease, granulomatous colitis, kidney failure, and cardiomyopathy is present. [11] Fatal hemocytophagic lymphohistiocytosis has been reported. [12] The Swiss variant has fewer systemic manifestations.

Platelets in patients with Hermansky-Pudlak syndrome abnormally aggregate with collagen, thrombin, epinephrine, and adenosine diphosphate (ADP). Electron microscopy shows that platelets in patients with Hermansky-Pudlak syndrome either lack dense granules or have smaller or fewer in number. Dense granules  are required for the second phase of platelet aggregation and are the storage sites for serotonin, calcium, and pyrophosphate.

Di Pietro et al [13] noted that BLOC-1 interacts with BLOC-2 and the AP-3 complex, facilitating protein trafficking on endosomes, and, when BLOC-1 is defective, Hermansky-Pudlak syndrome results.

A new homozygous nonsense mutation resulting in HPS1 was described in 2014. [14]

Jung et al [15] identified a homozygous deletion in the AP3B1 gene that causes HPS-2.

Hermansky-Pudlak syndrome protein complexes interface with phosphatidylinositol 4-kinase type II-alpha (PI4KII-alpha) in neuronal and non-neuronal cells. [16] Specifically, BLOC-1 deficiencies, but not BLOC-2 or BLOC-3 deficiencies, impact PI4KII-alpha inclusion into AP-3 complexes. BLOC-1, PI4KII-alpha, and AP-3 belong to a tripartite complex involved with down-regulation of PI4KII-alpha, BLOC-1, and AP-3 complexes.

In 2016, a type of Hermansky-Pudlak syndrome was defined based on mutations in the AP3D1 gene; this type causes seizures and immunodeficiency. [2]

Receptors of Chitinase 3-like-1 and Chitinase 3-like-1 are associated with lung disease in HPS. [17]

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