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HPS3
HPS3 biogenesis of lysosomal organelles complex 2 subunit 1
The HPS3 gene provides instructions for a protein that is part of the BLOC-2 complex, essential for the formation of specialised cellular structures called lysosome-related organelles (LROs). LROs perform distinct functions in specific cell types, such as producing melanin in pigment cells and facilitating blood clotting in platelets.
HPS3 is located on the long (q) arm of chromosome 3, at band 3q24. Arm ratio per GRCh38 - banding schematic.
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Overview
The HPS3 gene encodes a protein that is a subunit of the Biogenesis of Lysosomal Organelles Complex-2 (BLOC-2). This complex is critical for the correct formation and function of lysosome-related organelles (LROs) within cells. LROs are specialised compartments that share similarities with lysosomes but perform unique functions in various cell types, such as pigment cells and platelets.
What the gene does
The HPS3 protein contributes to the BLOC-2 complex, which is involved in sorting and transporting proteins to LROs during their development. These LROs include melanosomes, found in melanocytes, which are responsible for producing and distributing melanin that gives colour to skin, hair, and eyes. Another type of LRO, dense granules in platelets, plays a crucial role in blood clotting by releasing chemical signals that promote platelet aggregation. Disruptions in HPS3 function can therefore impair the formation or proper functioning of these LROs, leading to diverse clinical manifestations affecting pigmentation and haemostasis.
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Chromosome location
The HPS3 gene is located on chromosome 3 at position 3q24. The protein encoded by this gene is 1004 amino acids long. It is inherited in an autosomal recessive pattern.
Protein structure
The HPS3 protein contains a clathrin-binding motif, located between amino acids 172 and 176. This motif suggests an involvement in cellular trafficking processes, potentially by interacting with clathrin, a protein important for vesicle formation and transport.
Key variants
Genetic variations within the HPS3 gene can alter its function, leading to various health implications. These variants can include changes that affect the protein's stability, its ability to integrate into the BLOC-2 complex, or its interaction with other cellular components. Such changes can impair the proper development and function of lysosome-related organelles.
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.1058_1059del | p.Tyr353fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.1246_1247insT | p.Ala416fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.1330del | p.His444fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.2289del | p.Phe763fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.589dup | p.Tyr197fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.655G>T | p.Glu219Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.691C>T | p.Arg231Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.745_746del | p.Ser248_Asp249insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
c.817dup | p.Thr273fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.998T>A | p.Leu333Ter | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 3 |
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
Variants in the HPS3 gene are primarily associated with Hermansky-Pudlak Syndrome type 3. This condition typically presents with oculocutaneous albinism, characterised by fair skin, light-coloured hair, light-coloured eyes, and reduced vision. Individuals with Hermansky-Pudlak Syndrome type 3 may also experience bleeding problems due to impaired platelet function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HPS3 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 HPS3 gene is included in several NHS England Genomic Medicine Service approved panels. These include panels for "Albinism or congenital nystagmus" (R39), "Bleeding and platelet disorders" (R90), "Inherited bleeding disorders", and "Ocular and oculo-cutaneous albinism", indicating its recognised role in these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Hermansky-Pudlak Syndrome type 3?
Hermansky-Pudlak Syndrome type 3 is a genetic disorder caused by variants in the HPS3 gene. It is characterised by oculocutaneous albinism, which includes fair skin, light hair and eyes, and poor vision. Some individuals may also experience issues with blood clotting.
How does the HPS3 gene affect pigmentation?
The HPS3 gene is crucial for the formation of melanosomes, which are specialised organelles in pigment-producing cells that create and distribute melanin. When the HPS3 gene's function is impaired, melanin production can be disrupted, leading to the characteristic lack of pigmentation seen in albinism.
Can HPS3 variants affect blood clotting?
Yes, variants in the HPS3 gene can affect blood clotting. This is because the HPS3 protein is involved in forming dense granules within platelets, which are essential for releasing chemical signals that facilitate blood clot formation. Impaired function can lead to bleeding problems.
References
- Bultema JJ, Di Pietro SM. Cell type-specific Rab32 and Rab38 cooperate with the ubiquitous lysosome biogenesis machinery to synthesize specialized lysosome-related organelles. Small GTPases. 2013. PMID: 23247405
- Bultema JJ, Ambrosio AL, Burek CL. BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. The Journal of biological chemistry. 2012. PMID: 22511774
- 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
- Anikster Y, Huizing M, White J. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nature genetics. 2001. PMID: 11455388
- Huizing M, Anikster Y, Fitzpatrick DL. Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. American journal of human genetics. 2001. PMID: 11590544