On this page
HPS6
HPS6 biogenesis of lysosomal organelles complex 2 subunit 3
HPS6 is located on the long (q) arm of chromosome 10, at band 10q24.32. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 10 in the library →Available at Jeen Health
Clinical tests that include this
Overview
HPS6 encodes the third subunit of the biogenesis of lysosomal organelles complex 2 (BLOC-2), a protein assembly that coordinates the formation of lysosome-related organelles within cells. These specialised compartments include melanosomes in pigment-producing cells, dense granules in platelets, and lytic granules in immune cells. The HPS6 protein works alongside two other subunits to ensure these organelles develop properly and transport their contents to the correct cellular locations.
Pathogenic variants in HPS6 disrupt BLOC-2 function, preventing normal formation of lysosome-related organelles. This leads to Hermansky-Pudlak syndrome type 6, a rare autosomal recessive disorder characterised by reduced pigmentation, prolonged bleeding due to platelet dysfunction, and in some cases additional complications affecting the lungs or digestive system. The gene is included on multiple NHS genomic medicine panels reflecting the range of clinical features associated with its loss of function.
What the gene does
The HPS6 protein serves as one of three essential components of BLOC-2, a cellular trafficking complex that directs the movement of proteins and other cargo to lysosome-related organelles during their formation. BLOC-2 operates as part of a larger network of protein complexes (BLOC-1, BLOC-2, and BLOC-3) that coordinate different stages of organelle biogenesis.
Within this network, the HPS6-containing BLOC-2 complex facilitates the delivery of specific membrane proteins to developing organelles. In melanocytes, this ensures that enzymes required for melanin synthesis reach melanosomes, enabling normal pigment production. In platelets, BLOC-2 helps package molecules into dense granules that are released during blood clotting. In cytotoxic immune cells, the complex supports the formation of lytic granules containing proteins that eliminate infected or abnormal cells.
The protein functions through physical interactions with its partner subunits and with membrane-bound structures that serve as cargo carriers. Disruption of HPS6 destabilises the entire BLOC-2 complex, demonstrating that all three subunits are mutually dependent for proper assembly and function. This interdependence explains why variants affecting any BLOC-2 component produce similar clinical phenotypes.
Video: Genetics 101
Chromosome location
HPS6 is located on the long arm of chromosome 10 at position 24.32, designated as 10q24.32. The gene spans genomic DNA and encodes a messenger RNA that is translated into a protein of 775 amino acids. The chromosomal region containing HPS6 has been mapped through linkage studies in families with Hermansky-Pudlak syndrome, establishing the gene's position within the human genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The HPS6 protein comprises 775 amino acids but lacks well-defined functional domains annotated in structural databases. Current understanding of its function derives primarily from studies of protein-protein interactions within the BLOC-2 complex rather than from resolved three-dimensional structures. The protein's role appears to depend on specific interaction surfaces that enable binding to its two partner subunits, though the precise residues mediating these contacts have not been fully mapped.
Key variants
Pathogenic variants in HPS6 follow an autosomal recessive inheritance pattern, meaning that two altered copies (one inherited from each parent) are required to cause Hermansky-Pudlak syndrome type 6. Most reported variants are loss-of-function changes, including nonsense mutations that introduce premature stop codons, frameshift variants arising from small insertions or deletions, and splice-site alterations that disrupt normal messenger RNA processing. These variants typically abolish production of functional HPS6 protein, destabilising the BLOC-2 complex and impairing lysosome-related organelle formation.
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.1054_1055del | p.Arg352fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1228_1252del | p.Tyr410fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
c.1387C>T | p.Arg463Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.1513C>T | p.Gln505Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
c.1674del | p.Asn559fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
c.1782_1794del | p.Trp595fs | Pathogenic/Likely pathogenic | ★★☆☆ | HPS6-related disorders |
c.1784G>A | p.Trp595Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
c.1789del | p.Ala597fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
c.466_475dup | p.Phe159fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
c.503_504del | p.Leu168fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 6 |
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 HPS6 cause Hermansky-Pudlak syndrome type 6, a multisystem disorder characterised by oculocutaneous albinism and platelet storage pool deficiency. Affected individuals typically present with reduced pigmentation of the skin, hair, and eyes from birth, alongside prolonged bleeding times due to impaired platelet function. Eye findings may include nystagmus, reduced visual acuity, and increased sensitivity to light. Some individuals develop additional complications, particularly pulmonary fibrosis or granulomatous colitis, though the frequency and severity of these features vary. The condition is rare, with most cases identified through investigation of unexplained bleeding in individuals with albinism.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HPS6 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
HPS6 appears on multiple NHS Genomic Medicine Service panels as a green-rated gene (suitable for clinical reporting). These include the Albinism or Congenital Nystagmus panel, reflecting the pigmentation and vision features of Hermansky-Pudlak syndrome, and the Bleeding and Platelet Disorders panel, recognising the platelet dysfunction component. The gene is also listed on panels for Inherited Bleeding Disorders, Gastrointestinal Epithelial Barrier Disorders, and Primary Immunodeficiency or Monogenic Inflammatory Bowel Disease, acknowledging the range of potential clinical manifestations. This broad representation across panels reflects the multisystem nature of conditions caused by HPS6 variants and enables appropriate diagnostic testing for individuals presenting with any combination of characteristic features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does HPS6 follow?
HPS6 variants are inherited in an autosomal recessive pattern. This means a person must inherit two altered copies of the gene, one from each parent, to develop Hermansky-Pudlak syndrome type 6. Individuals with one altered copy are carriers and typically do not show symptoms.
How does HPS6 differ from other genes causing Hermansky-Pudlak syndrome?
HPS6 encodes a specific subunit of the BLOC-2 complex, while other Hermansky-Pudlak syndrome genes encode different protein complexes (BLOC-1, BLOC-3, AP-3) involved in lysosome-related organelle formation. Each gene produces a distinct subtype of the syndrome, numbered according to the gene affected, though the core features of albinism and bleeding tendency are shared.
Why does HPS6 appear on multiple NHS genomic panels?
Hermansky-Pudlak syndrome type 6 affects multiple organ systems, causing pigmentation abnormalities, bleeding problems, and potentially lung or bowel complications. HPS6 therefore appears on panels for albinism, platelet disorders, inflammatory bowel disease, and other relevant clinical areas to ensure the gene is considered when any of these features are present.