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HPS1
HPS1 biogenesis of lysosomal organelles complex 3 subunit 1
The HPS1 gene provides instructions for a protein critical to the formation of lysosome-related organelles (LROs), which are specialised cellular compartments involved in pigmentation and blood clotting. HPS1 produces a protein that forms part of the BLOC-3 complex, essential for creating LROs.
HPS1 is located on the long (q) arm of chromosome 10, at band 10q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The HPS1 gene, also known as HPS1 biogenesis of lysosomal organelles complex 3 subunit 1, encodes a protein that forms a subunit of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). This complex is crucial for the proper formation and function of lysosome-related organelles (LROs) within cells. LROs are specialised compartments found in specific cell types, performing diverse functions such as pigment production and blood clotting.
Variations in the HPS1 gene are associated with Hermansky-Pudlak syndrome, an inherited condition characterised by oculocutaneous albinism, bleeding issues, and in some cases, severe lung disease. Understanding the HPS1 gene is important for diagnosing and managing this complex disorder.
What the gene does
The protein encoded by the HPS1 gene is a subunit of the BLOC-3 complex. This complex is instrumental in the biogenesis of lysosome-related organelles (LROs), which are cellular structures similar to lysosomes but with specialised roles. The BLOC-3 complex facilitates the transport of essential proteins to LROs during their development.
LROs are found in various cell types. For example, in melanocytes (pigment-producing cells), LROs called melanosomes are responsible for synthesising and distributing melanin, the pigment that determines the colour of skin, hair, and eyes. In platelets, another type of LRO, known as dense granules, stores and releases chemical signals necessary for blood clotting. LROs are also present in other specialised cells, including certain cells in the lungs, contributing to their specific functions.
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Chromosome location
The HPS1 gene is situated on the long arm of chromosome 10, specifically at position 10q24.2. This genomic location indicates its precise address within the human genome.
Protein structure
The HPS1 protein has a length of 700 amino acids. Its structural composition includes several distinctive features. It contains four [DE]-X(4)-L-L repeat motifs: the first is located at amino acids 45-51, the second at 147-153, the third at 516-522, and the fourth at 644-650. A significant Disordered region is present between amino acids 249-317. Additionally, a Melanosome targeting signal motif is found towards the C-terminus, specifically at amino acids 698-700.
Key variants
Genetic variations within the HPS1 gene can impact the structure and function of the encoded protein. These variations, which include various types of sequence changes, can disrupt the protein's ability to participate in the BLOC-3 complex and affect LRO biogenesis. Pathogenic variants are commonly associated with the development of Hermansky-Pudlak syndrome. At least 31 pathogenic variants in HPS1 have been identified in association with Hermansky-Pudlak syndrome type 1.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1172del | p.Leu391fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 1 |
c.1198del | p.Asp400fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 1 |
c.1771A>T | p.Arg591Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 1 |
c.1777del | p.Leu593fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.1940+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.310dup | p.Asp104fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 1 |
c.399-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.904_917dup | p.Pro307fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.938-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 1 |
c.987+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the HPS1 gene are primarily associated with Hermansky-Pudlak syndrome type 1. This condition is characterised by oculocutaneous albinism, which results in light-coloured hair, skin, and eyes, often accompanied by impaired vision. Individuals may also experience bleeding difficulties due to abnormal platelet function and, in some cases, develop pulmonary fibrosis, a severe lung disease.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HPS1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The HPS1 gene is included in several Green RAG status panels within the NHS Genomic Medicine Service's PanelApp, indicating that there is strong evidence for its association with certain conditions. These panels cover a range of disorders including Albinism or congenital nystagmus (R39), Bleeding and platelet disorders (R90), Ocular and oculo-cutaneous albinism, and Pulmonary Fibrosis, Familial (R421). It is also part of panels for Primary immunodeficiency or monogenic inflammatory bowel disease (R15) and Pigmentary skin disorders (R236), among others.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the HPS1 gene?
The HPS1 gene provides instructions for a protein that is a crucial component of the BLOC-3 complex. This complex helps in the formation and function of lysosome-related organelles (LROs), which are specialised cellular structures involved in various processes like melanin production and blood clotting.
What health condition is associated with HPS1 gene variants?
Variants in the HPS1 gene are primarily associated with Hermansky-Pudlak syndrome type 1. This syndrome typically causes oculocutaneous albinism, bleeding problems, and can also lead to severe lung disease known as pulmonary fibrosis.
How does HPS1 affect pigmentation?
In pigment-producing cells called melanocytes, the HPS1 protein contributes to the formation of melanosomes, which are a type of LRO. Melanosomes are responsible for producing and distributing melanin, the pigment that gives colour to skin, hair, and eyes. Disruptions in HPS1 can therefore affect melanin production, leading to albinism.
References
- Carmona-Rivera C, Simeonov DR, Cardillo ND. A divalent interaction between HPS1 and HPS4 is required for the formation of the biogenesis of lysosome-related organelle complex-3 (BLOC-3). Biochimica et biophysica acta. 2013. PMID: 23103514
- Gerondopoulos A, Langemeyer L, Liang JR. BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor. Current biology : CB. 2012. PMID: 23084991
- Dessinioti C, Stratigos AJ, Rigopoulos D. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Experimental dermatology. 2009. PMID: 19555431
- Huizing M, Helip-Wooley A, Westbroek W. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annual review of genomics and human genetics. 2008. PMID: 18544035
- Huizing M, Parkes JM, Helip-Wooley A. Platelet alpha granules in BLOC-2 and BLOC-3 subtypes of Hermansky-Pudlak syndrome. Platelets. 2007. PMID: 17365864
- Li W, Feng Y, Hao C. The BLOC interactomes form a network in endosomal transport. Journal of genetics and genomics = Yi chuan xue bao. 2007. PMID: 17707211
- Santiago Borrero PJ, Rodríguez-Pérez Y, Renta JY. Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico. The Journal of investigative dermatology. 2006. PMID: 16417222
- Ito S, Suzuki T, Inagaki K. High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein. The Journal of investigative dermatology. 2005. PMID: 16185271
- Gahl WA, Brantly M, Kaiser-Kupfer MI. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). The New England journal of medicine. 1998. PMID: 9562579