A Novel Likely Pathogenic Variant in the BLOC1S5 Gene Associated with Hermansky-Pudlak Syndrome Type 11 and an Overview of Human BLOC-1 Deficiencies

Cells. 2021 Oct 1;10(10):2630. doi: 10.3390/cells10102630.

Abstract

Hermansky-Pudlak syndrome (HPS) is a heterogeneous disorder combining oculocutaneous albinism (OCA) and a platelet function disorder of varying severity as its most prominent features. The genes associated with HPS encode for different BLOC- (biogenesis of lysosome-related organelles complex) complexes and for the AP-3 (adaptor protein-3) complex, respectively. These proteins are involved in maturation, trafficking, and the function of lysosome-related organelles (LROs) such as melanosomes and platelet δ-granules. Some patients with different types of HPS can develop additional complications and symptoms like pulmonary fibrosis, granulomatous colitis, and immunodeficiency. A new type of HPS has recently been identified associated with genetic alterations in the BLOC1S5 gene, which encodes the subunit Muted of the BLOC-1 complex. Our aim was to unravel the genetic defect in two siblings with a suspected HPS diagnosis (because of OCA and bleeding symptoms) using next generation sequencing (NGS). Platelet functional analysis revealed reduced platelet aggregation after stimulation with ADP and a severe secretion defect in platelet δ-granules. NGS identified a novel homozygous essential splice site variant in the BLOC1S5 gene present in both affected siblings who are descendants of a consanguine marriage. The patients exhibited no additional symptoms. Our study confirms that pathogenic variants of BLOC1S5 cause the recently described HPS type 11.

Keywords: BLOC1S5; HPS-11; Hermansky-Pudlak syndrome; bleeding tendency; hypopigmentation; oculocutaneous albinism.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Base Sequence
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Hermanski-Pudlak Syndrome / blood
  • Hermanski-Pudlak Syndrome / genetics*
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Male
  • Mutation / genetics*
  • Platelet Aggregation / drug effects
  • Thrombin / pharmacology
  • Vesicular Transport Proteins / genetics*

Substances

  • BLOC1S5 protein, human
  • Vesicular Transport Proteins
  • Thrombin

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