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HPS4
HPS4 biogenesis of lysosomal organelles complex 3 subunit 2
HPS4 is located on the long (q) arm of chromosome 22, at band 22q12.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The HPS4 gene, located on chromosome 22, provides instructions for making a protein that forms part of a larger cellular machine called the biogenesis of lysosomal organelles complex 3 (BLOC-3). This complex plays a critical role in assembling and trafficking lysosome-related organelles, which are specialised compartments within cells. These organelles include melanosomes in pigment-producing cells, dense granules in platelets, and lytic granules in immune cells. When HPS4 variants disrupt BLOC-3 function, cells cannot properly build or maintain these structures, leading to problems with pigmentation, blood clotting, and immune responses. The gene is clinically significant in the context of autosomal recessive carrier screening.
What the gene does
The HPS4 protein functions as a subunit of the BLOC-3 complex, working alongside other proteins to coordinate the movement of cargo molecules to lysosome-related organelles. This trafficking process ensures that melanin pigment reaches melanosomes, that clotting factors and dense-core granule contents are packaged into platelet granules, and that cytotoxic molecules are delivered to immune cell granules. The protein facilitates membrane-tethering events and helps recruit molecular motors that transport cargo vesicles along the cell's internal scaffolding. By regulating these pathways, HPS4 supports normal development and function of tissues that rely on lysosome-related organelles. Disruption of this trafficking machinery prevents cells from achieving the specialised compartmentalisation required for pigmentation, haemostasis, and immune surveillance.
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Chromosome location
HPS4 is situated at chromosomal band 22q12.1 on the long arm of chromosome 22. The gene spans genomic DNA that encodes a 708-amino-acid protein. This region of chromosome 22 contains several other genes involved in cellular trafficking and organelle biology, although the precise number of exons and detailed genomic architecture have not been extensively characterised in public reference datasets.
Protein structure
The HPS4 protein comprises 708 amino acids and contains two notable disordered regions: one spanning amino acids 269 to 331 and another from amino acids 407 to 490. Disordered regions are stretches of the protein that lack fixed three-dimensional structure under physiological conditions, often serving as flexible linkers or sites for dynamic protein-protein interactions. These regions may allow HPS4 to adapt its conformation when binding to other BLOC-3 components or interacting with membrane surfaces during vesicle trafficking. Beyond these disordered segments, the detailed domain architecture has not been fully mapped experimentally.
Key variants
Pathogenic variants in HPS4 are typically loss-of-function changes such as nonsense mutations, frameshift insertions or deletions, and splice-site alterations that prevent normal protein production. Because Hermansky-Pudlak syndrome type 4 follows an autosomal recessive pattern, individuals require variants in both copies of the gene to develop the condition. Carriers with a single variant generally do not show symptoms but can pass the variant to their children.
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.1088_1101del | p.Leu363fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.1132C>T | p.Gln378Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
c.1184del | p.Pro395fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.1330G>T | p.Glu444Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.148C>T | p.Gln50Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.1546C>T | p.Gln516Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.1767_1768del | p.Leu590fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.2054del | p.Pro685fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.47del | p.Asn16fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
c.673_686del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 4 |
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 HPS4 cause Hermansky-Pudlak syndrome type 4, a rare autosomal recessive disorder. Affected individuals typically present with oculocutaneous albinism (reduced pigmentation of the skin, hair, and eyes), nystagmus, and reduced visual acuity. A bleeding diathesis due to absent or dysfunctional platelet dense granules is also common, leading to easy bruising and prolonged bleeding. Some individuals may develop pulmonary fibrosis or granulomatous colitis, though these complications are less consistently observed in type 4 compared to other Hermansky-Pudlak subtypes.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HPS4 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
HPS4 appears on multiple NHS England Genomic Medicine Service panels, reflecting its relevance across several clinical domains. The gene holds green (high-evidence) status on panels including Albinism or congenital nystagmus, Bleeding and platelet disorders, Inherited bleeding disorders, and Ocular and oculo-cutaneous albinism. It is also listed on panels for Familial pulmonary fibrosis, Gastrointestinal epithelial barrier disorders, and Primary immunodeficiency or monogenic inflammatory bowel disease, underscoring the multisystem nature of Hermansky-Pudlak syndrome. This classification supports the inclusion of HPS4 in carrier screening programmes in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for HPS4 variants?
HPS4-related conditions follow an autosomal recessive pattern. This means an individual must inherit a pathogenic variant from both parents to develop Hermansky-Pudlak syndrome type 4. Carriers with one variant are generally unaffected.
Why is HPS4 included in carrier screening?
HPS4 is included in autosomal recessive carrier screening because pathogenic variants can cause Hermansky-Pudlak syndrome type 4, a condition with significant clinical impact including bleeding problems and visual impairment. Identifying carriers helps couples understand reproductive risks.
Can HPS4 variants affect only one system, such as vision or bleeding?
Most individuals with biallelic HPS4 variants present with both pigmentation abnormalities and bleeding tendency, as the underlying defect affects multiple cell types. However, the severity and range of complications can vary between individuals.