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

Doris Boeckelmann,Udo Koehler,Barbara Zieger,Lea Schieber-Nakamura,Barbara Käsmann-Kellner,Mira Wolter

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.

Highlights

Hermansky-Pudlak syndrome (HPS, OMIM Phenotype Series—PS203300) is a rare heterogeneous disorder affecting maturation, trafficking, and the function of lysosome-related organelles (LROs) such as melanosomes and platelet δ-granules
HPS is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis of variable severity
Our study identified a novel homozygous essential splice site variant located at the acceptor splice site of intron 1 in BLOC1S5 in two brothers presenting with an HPS phenotype

Summary

Introduction

Hermansky-Pudlak syndrome (HPS, OMIM Phenotype Series—PS203300) is a rare heterogeneous disorder affecting maturation, trafficking, and the function of lysosome-related organelles (LROs) such as melanosomes and platelet δ-granules. Cell type specific LROs may be affected, leading to pulmonary fibrosis (aberrant alveolar macrophage or mast cell function), to granulomatous colitis (intestinal granulomas and inflammatory cells), and immunodeficiency (cytotoxic T-cell-granules). Since its first description in 1959 by Hermansky and Pudlak [1], knowledge of the clinical symptoms, underlying genes and pathomechanism of HPS has deepened over the last few decades. Up until 2020, alterations in genes had been reported to cause HPS type 1 to type 10; Pennamen et al reported just recently pathogenic variants in the BLOC1S5 gene (OMIM *607289) associated with a new type of HPS named type (#619172) [2]

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