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BLOC1S6 – Hermansky-Pudlak Syndrome 9

Biallelic loss-of-function variants in BLOC1S6 cause Hermansky-Pudlak syndrome 9, an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding diathesis and absent platelet dense granules. Two unrelated patients have been reported: a homozygous splice-site variant c.312+1G>T in a boy with albinism and absent delta granules (PMID:21665000) and a Chinese patient with compound heterozygous truncating variants c.148G>T (p.Glu50Ter) and c.351dupT (p.Ile118TyrfsTer10) presenting with photophobia and nystagmus (PMID:33543539). Parental carrier segregation confirms autosomal recessive inheritance without additional affected relatives.

Functional studies support a loss-of-function mechanism: the pallid (pa) mouse model harboring a nonsense mutation exhibits prolonged bleeding, pigment dilution and defective melanosome and dense-granule biogenesis, with pallidin failing to bind t-SNARE syntaxin 13 by co-immunoprecipitation and mislocalizing by immunofluorescence (PMID:10610180). RUNX1 regulatory assays further demonstrate that PLDN downregulation in human cells recapitulates dense-granule deficiency, confirming its essential role in lysosome-related organelle formation (PMID:28075530). Taken together, genetic and experimental data provide limited clinical validity for BLOC1S6 in HPS-9. Key take-home: BLOC1S6 sequencing is warranted in patients with autosomal recessive albinism and bleeding diathesis with absent platelet dense granules.

References

  • American Journal of Human Genetics • 2011 • A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9. PMID:21665000
  • The Journal of Dermatology • 2021 • The first Hermansky-Pudlak syndrome type 9 patient with two novel variants in Chinese population. PMID:33543539
  • 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 • 2017 • Dysregulation of PLDN (pallidin) is a mechanism for platelet dense granule deficiency in RUNX1 haplodeficiency. PMID:28075530

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two unrelated probands with biallelic truncating and splice-site variants; AR inheritance; supportive functional data

Genetic Evidence

Limited

Two unrelated probands with biallelic loss-of-function variants in BLOC1S6 (PMID:21665000; PMID:33543539)

Functional Evidence

Moderate

Mouse pallid model recapitulates pigment and platelet defects; co-IP, IF and RUNX1-regulation assays confirm pallidin role in granule biogenesis (PMID:10610180; PMID:28075530)