Hermansky-Pudlak Syndrome Genetics and Pathophysiology

Hermansky–Pudlak syndrome (HPS) is a genetically heterogeneous autosomal recessive disorder characterised by oculocutaneous albinism, bleeding diathesis and, in certain subtypes, immunodeficiency, granulomatous colitis and progressive pulmonary fibrosis. At least eleven genes underlie recognised HPS subtypes; these encode subunits of multiprotein complexes essential for vesicular trafficking to lysosome-related organelles (LROs). BLOC-1 (biogenesis of lysosome-related organelles complex-1) includes subunits such as dysbindin and BLOC1S6, while BLOC-2 and BLOC-3 contain HPS3, HPS5, HPS6 and HPS1, HPS4 respectively. HPS type 2 arises from defects in the AP-3 adaptor complex. Pathogenic variants disrupt the formation or function of melanosomes in melanocytes, platelet dense granules and lamellar bodies in alveolar epithelial cells, leading to hypopigmentation, platelet storage-pool deficiency and aberrant surfactant processing. In pulmonary fibrosis, dysfunctional type II pneumocytes fail to maintain alveolar homeostasis, provoking immune activation and progressive extracellular matrix deposition. Model organisms have elucidated the structural organisation of BLOC complexes and the consequences of subunit loss, while patient-derived cellular systems and induced pluripotent stem cells support investigation of genotype–phenotype correlations. Understanding the molecular basis of LRO biogenesis has informed emerging therapeutic avenues, including gene editing, lentiviral gene transfer and pharmacological modulation of vesicle trafficking pathways.

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Hermansky-Pudlak Syndrome Genetics and Pathophysiology publication trend

The graph below shows the total number of articles in hermansky-pudlak syndrome genetics and pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Oculocutaneous albinism: Reduced melanin synthesis in skin, hair and eyes due to melanosome dysfunction.

Bleeding diathesis: Increased tendency to bleed, often from platelet dense granule deficiency.

Lysosome-related organelles (LROs): Specialized organelles such as melanosomes, platelet dense granules and lamellar bodies.

BLOC complexes: Multisubunit protein assemblies (BLOC-1, ‑2, ‑3) required for trafficking cargo to LROs.

Pulmonary fibrosis: Excessive deposition of extracellular matrix in lung interstitium leading to respiratory insufficiency.

Copy number variation: Genomic deletion or duplication affecting one or more exons, detectable by specific molecular assays.

References

1. Pathogenesis and Therapy of Hermansky–Pudlak Syndrome (HPS)-Associated Pulmonary Fibrosis. International Journal of Molecular Sciences (2024).
2. A novel deletion in the BLOC1S6 Gene Associated with Hermansky-Pudlak syndrome type 9 (HPS-9). BMC Genomics (2024).
3. Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7). Frontiers in Pharmacology (2022).
4. Interstitial Lung Disease and Pulmonary Fibrosis in Hermansky-Pudlak Syndrome Type 2, an Adaptor Protein-3 Complex Disease. Molecular Medicine (2011).