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BLOC1S6
biogenesis of lysosomal organelles complex 1 subunit 6
BLOC1S6 is located on the long (q) arm of chromosome 15, at band 15q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
BLOC1S6 is located on chromosome 15 and encodes pallidin, a 172-amino-acid protein that serves as one of eight subunits in the BLOC-1 complex. This complex functions as a molecular scaffold that coordinates the movement of protein cargo to lysosome-related organelles, specialised compartments found in melanocytes, platelets, and other cell types. When BLOC1S6 function is impaired, cells cannot properly construct these organelles, resulting in reduced melanin deposition in skin and eyes, absent platelet dense granules that normally support blood clotting, and defective immune cell granules. The gene follows an autosomal recessive inheritance pattern, meaning pathogenic variants in both gene copies are required to cause disease. BLOC1S6-related conditions are included on multiple NHS Genomic Medicine Service panels, reflecting the clinical importance of accurate diagnosis for managing bleeding risk, visual impairment, and potential immunodeficiency.
What the gene does
Pallidin functions within the BLOC-1 complex to regulate vesicle trafficking pathways that deliver membrane proteins and other cargo to lysosome-related organelles. The complex interacts with components of the endosomal sorting machinery, including SNARE proteins and adaptor protein complexes, to ensure that newly synthesised proteins reach their correct subcellular destinations. In melanocytes, BLOC-1 coordinates the maturation of melanosomes, the organelles where melanin pigment is synthesised and stored. The complex facilitates the trafficking of enzymes required for melanin production, as well as structural proteins that shape the melanosome's internal architecture. In platelets, BLOC-1 is essential for assembling dense granules, which store small molecules like adenosine diphosphate and serotonin that amplify clotting responses when released. Loss of pallidin disrupts the entire BLOC-1 assembly, destabilising the other subunits and preventing the complex from performing its trafficking functions. This results in hypopigmentation due to poorly developed melanosomes, prolonged bleeding times from absent platelet granules, and potential susceptibility to infections from impaired immune cell granule formation.
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Chromosome location
BLOC1S6 is positioned at chromosomal band 15q21.1 on the long arm of chromosome 15. The gene spans a relatively compact genomic region and produces a transcript encoding the 172-amino-acid pallidin protein. This cytoplasmic protein does not contain a signal peptide or transmembrane domains, consistent with its role as a soluble scaffold component within the BLOC-1 complex. The gene's location at 15q21.1 places it within a region containing several other genes involved in cellular trafficking and membrane organisation.
Protein structure
Pallidin is a 172-amino-acid protein with a domain organisation that reflects its role in protein-protein interactions within the BLOC-1 complex. The protein contains a disordered region spanning amino acids 1-36 at the N-terminus, which may provide flexibility for complex assembly. The central portion of the protein features an extended coiled coil domain covering amino acids 63-167, a structural motif commonly found in proteins that mediate multimerisation and scaffold formation. This coiled coil region is likely critical for pallidin's ability to interact with other BLOC-1 subunits and maintain the structural integrity of the complex. The C-terminal region includes another disordered segment from amino acids 135-172, which overlaps with the coiled coil domain and may contribute to dynamic conformational changes during vesicle trafficking events.
Key variants
Pathogenic variants in BLOC1S6 are associated with Hermansky-Pudlak syndrome type 9, a rare autosomal recessive disorder. Most reported variants include nonsense mutations, frameshift insertions or deletions, and splice-site changes that result in loss of functional pallidin protein. Because the BLOC-1 complex requires all eight subunits to assemble correctly, even partial reduction in pallidin levels can destabilise the entire complex and abolish its trafficking functions. Carrier status for BLOC1S6 variants does not typically cause clinical features, as one functional gene copy produces sufficient pallidin to support normal BLOC-1 activity.
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.200C>G | p.Ser67Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 9 |
c.318_320delinsAT | p.Glu107fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome 9 |
c.335dup | p.His112fs | Pathogenic | ★★☆☆ | Hermansky-Pudlak syndrome |
g.45592135del | - | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
g.(?_45884313)_(45898712_?)del | - | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
c.203_207del | p.Lys68fs | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
c.205C>T | p.Gln69Ter | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
c.224+1G>A | - | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
c.245T>A | p.Leu82Ter | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
c.7_22dup | p.Ser8fs | Pathogenic | ★☆☆☆ | Hermansky-Pudlak syndrome 9 |
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 BLOC1S6 cause Hermansky-Pudlak syndrome type 9, characterised by oculocutaneous albinism, bleeding tendency, and variable immunodeficiency. Affected individuals present with reduced pigmentation of the skin, hair, and eyes, leading to visual impairment including nystagmus, reduced visual acuity, and photophobia. The absence of platelet dense granules results in prolonged bleeding after injury or surgery, even though platelet counts remain normal. Some individuals experience recurrent infections or inflammatory complications due to impaired immune cell function, though the immunological features are generally less severe than in some other Hermansky-Pudlak syndrome subtypes. Unlike certain other forms of Hermansky-Pudlak syndrome, pulmonary fibrosis and granulomatous colitis appear to be less common in type 9, though long-term data remain limited given the rarity of the condition.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic BLOC1S6 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
BLOC1S6 holds green classification status on several NHS Genomic Medicine Service gene panels, reflecting strong evidence linking variants in this gene to clinically actionable conditions. The gene appears on the Albinism or congenital nystagmus panel (R39), recognising its role in oculocutaneous albinism. It is also included on the Bleeding and platelet disorders panel (R90) and the Inherited bleeding disorders panel, reflecting the bleeding tendency associated with absent platelet dense granules. Additionally, BLOC1S6 features on the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), acknowledging the potential immune dysfunction in Hermansky-Pudlak syndrome type 9. Inclusion on the Developmental Disorders Genotype to Phenotype (DDG2P) panel further supports the clinical utility of BLOC1S6 testing in comprehensive genomic diagnostic pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for BLOC1S6-related conditions?
BLOC1S6-related conditions follow an autosomal recessive inheritance pattern, meaning an individual must inherit pathogenic variants in both copies of the gene to develop the condition. Carriers with one variant copy are typically unaffected but can pass the variant to their children.
How does BLOC1S6 differ from other Hermansky-Pudlak syndrome genes?
BLOC1S6 encodes a subunit of the BLOC-1 complex and causes Hermansky-Pudlak syndrome type 9. While this shares the core features of albinism and bleeding tendency with other subtypes, type 9 appears less commonly associated with pulmonary fibrosis and inflammatory bowel disease compared to some other Hermansky-Pudlak syndrome variants.
Why is BLOC1S6 included on bleeding disorder panels?
BLOC1S6 variants cause absent or defective platelet dense granules, leading to a storage pool deficiency that impairs normal blood clotting. This results in prolonged bleeding times despite normal platelet counts, making the gene clinically relevant for inherited bleeding disorder diagnostics.