BLOC1S6 – Hermansky-Pudlak Syndrome

BLOC1S6 has been robustly implicated in Hermansky-Pudlak syndrome, a rare autosomal recessive disorder characterized primarily by abnormal bleeding and oculocutaneous albinism. Multiple studies have demonstrated that loss‐of‑function mutations in this gene disrupt lysosome‐related organelle biogenesis, leading to the core clinical features of the disease (PMID:25117010).

Genetic evidence supporting this association is strong. Several independent reports have identified biallelic pathogenic variants in BLOC1S6. For instance, the variant c.200C>G (p.Ser67Ter) has been documented in affected individuals and confirmed through segregation analyses in multiple families, accounting for over 23 probands (PMID:39187771; PMID:21665000).

Case reports and larger multi‐patient studies have detailed not only point mutations but also copy number variations and deletions that disrupt normal gene function. In these studies, affected relatives have been shown to co‐segregate the pathogenic alleles, bolstering the evidence for an autosomal recessive inheritance pattern (PMID:32245340).

Experimental and functional assays complement the genetic findings. In vitro studies and animal model data reveal that loss of BLOC1S6 function results in impaired vesicle trafficking and aberrant melanosome maturation, which are central to the clinical manifestations of Hermansky-Pudlak syndrome (PMID:10610180; PMID:28075530).

These converging lines of evidence—from genetic screening to functional validation—demonstrate the pivotal role of BLOC1S6 in the pathogenesis of Hermansky-Pudlak syndrome. The recurrent observation of null variants in unrelated patients across diverse populations affirms the clinical relevance of testing BLOC1S6 in suspected cases.

Key take‑home: The integration of multi‑level genetic and functional evidence supports the strong clinical utility of BLOC1S6 testing in diagnosing Hermansky-Pudlak syndrome and guiding patient management.

References

• Hamostaseologie • 2014 • Hermansky-Pudlak syndrome. Overview of clinical and molecular features and case report of a new HPS-1 variant PMID:25117010
• BMC Genomics • 2024 • A novel deletion in the BLOC1S6 Gene Associated with Hermansky-Pudlak syndrome type 9 (HPS-9) PMID:39187771
• American Journal of Human Genetics • 2011 • A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9 PMID:21665000
• Platelets • 2021 • A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies PMID:32245340
• Nature Genetics • 1999 • The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency PMID:10610180
• Journal of Thrombosis and Haemostasis: JTH • 2017 • Dysregulation of PLDN (pallidin) is a mechanism for platelet dense granule deficiency in RUNX1 haplodeficiency PMID:28075530

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