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HPS5
HPS5 biogenesis of lysosomal organelles complex 2 subunit 2
HPS5 is located on the short (p) arm of chromosome 11, at band 11p15.1. Arm ratio per GRCh38 - banding schematic.
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Overview
HPS5 encodes the second subunit of biogenesis of lysosomal organelles complex 2 (BLOC-2), a multiprotein assembly that coordinates the formation of lysosome-related organelles throughout the body. These specialised compartments serve distinct functions depending on cell type: melanosomes produce pigment in skin and eyes, dense granules enable blood platelets to clot effectively, and lamellar bodies support lung function. The protein produced from HPS5 works alongside other BLOC-2 components to transport molecular cargo to these organelles during their maturation. When both copies of HPS5 carry disease-causing changes, the resulting disruption to organelle assembly can manifest as a multisystem condition characterised by albinism, prolonged bleeding, and in some cases pulmonary complications. HPS5 is included on UK carrier screening panels because of its autosomal recessive inheritance pattern.
What the gene does
The HPS5 protein functions as a core structural element within BLOC-2, a complex that orchestrates the delivery of proteins and lipids to maturing lysosome-related organelles. This trafficking process relies on the complex's ability to recognise specific cargo molecules and facilitate their incorporation into developing melanosomes, platelet dense granules, and other specialised compartments. Within melanocytes, BLOC-2 activity ensures that enzymes required for melanin synthesis reach melanosomes at the appropriate developmental stage, enabling normal pigment production. In megakaryocytes and platelets, the complex directs molecules such as serotonin and adenosine diphosphate to dense granules, which are released during the clotting cascade to amplify platelet activation. The protein participates in membrane-remodelling events that shape these organelles as they mature from early endosomal precursors. BLOC-2 function represents one step in a coordinated pathway involving multiple BLOC complexes, each contributing to distinct stages of organelle biogenesis.
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Chromosome location
HPS5 resides on the short arm of chromosome 11 at position 15.1 (11p15.1), a region that undergoes active recombination and contains numerous other genes involved in developmental processes. The genomic sequence spans multiple exons that together encode the 1,129-amino-acid protein. This chromosomal band lies relatively close to the centromere, which can influence patterns of genetic variation in the region.
Protein structure
The HPS5 protein comprises 1,129 amino acids with several disordered regions that may provide structural flexibility for protein-protein interactions within the BLOC-2 complex. Two notable disordered regions span amino acids 483 to 503 and 561 to 609, segments that lack fixed three-dimensional structure and may undergo conformational changes during complex assembly or cargo recognition. These intrinsically disordered stretches often serve as sites for post-translational modification or binding to partner proteins, though the specific functional roles of these particular regions in HPS5 have not been fully characterised. The overall architecture suggests a scaffolding protein that stabilises the BLOC-2 assembly through multiple interaction surfaces.
Key variants
Pathogenic variants in HPS5 include nonsense changes that introduce premature stop codons, frameshifts resulting from small insertions or deletions, and missense substitutions that disrupt critical interaction surfaces within the protein. Loss-of-function variants that abolish protein production or severely compromise BLOC-2 assembly are typically associated with more pronounced clinical features. The distribution of reported variants spans the length of the gene, without a single predominant mutational hotspot, reflecting the importance of the protein's structural integrity across its entire sequence.
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.1252del | p.Glu418fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 5 |
c.2056del | p.Glu686fs | Pathogenic/Likely pathogenic | ★★☆☆ | HPS5-related disorder |
c.2077del | p.Arg693fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 5 |
c.220-1G>T | - | Pathogenic | ★★☆☆ | not provided |
c.2375del | p.Glu792fs | Pathogenic/Likely pathogenic | ★★☆☆ | HPS5-related disorder |
c.2718-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 5 |
c.543del | p.Gln181fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.739dup | p.Glu247fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.825-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 5 |
c.82dup | p.Leu28fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
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
Biallelic pathogenic variants in HPS5 cause Hermansky-Pudlak syndrome, a multisystem condition characterised by oculocutaneous albinism, bleeding diathesis due to absent platelet dense granules, and variable involvement of the lungs and other organs. The albinism component results from defective melanosome maturation, producing reduced pigmentation of the skin, hair, and eyes along with associated visual abnormalities such as nystagmus and reduced visual acuity. The bleeding tendency reflects impaired platelet function, as dense granules fail to form properly and cannot release their contents to support normal clot formation. Some individuals develop pulmonary fibrosis or colitis, though these complications are less predictable and may depend on genetic background or environmental factors. The condition follows an autosomal recessive inheritance pattern, meaning affected individuals inherit one pathogenic variant from each parent.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HPS5 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
HPS5 appears on multiple NHS Genomic Medicine Service gene panels that support clinical diagnosis and reproductive decision-making. It holds green (high-evidence) status on the Albinism or congenital nystagmus panel, the Bleeding and platelet disorders panel, the Inherited bleeding disorders panel, and the Ocular and oculo-cutaneous albinism panel. These panel memberships reflect the gene's established role in conditions affecting pigmentation and haemostasis, ensuring that testing is available through NHS laboratories when clinical features suggest Hermansky-Pudlak syndrome or related phenotypes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean if I carry one HPS5 variant?
Carrying one pathogenic variant in HPS5 typically produces no health effects, as the other copy of the gene provides sufficient protein function. Carriers may wish to consider reproductive genetic counselling, particularly if a partner also carries an HPS5 variant or has a family history of Hermansky-Pudlak syndrome.
How is Hermansky-Pudlak syndrome managed?
Management focuses on addressing specific symptoms: protective eyewear and visual aids for albinism-related photophobia and reduced vision, avoidance of medications that impair platelet function, and monitoring for pulmonary or gastrointestinal complications. A multidisciplinary care team including dermatologists, haematologists, and ophthalmologists can coordinate surveillance and intervention.
Are all types of Hermansky-Pudlak syndrome caused by HPS5?
No. Hermansky-Pudlak syndrome is genetically heterogeneous, with pathogenic variants in at least ten different genes capable of producing similar phenotypes. HPS5 accounts for one subtype, and genetic testing often sequences multiple genes to identify the underlying cause.