BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak syndrome

Genet Med. 2020 Oct;22(10):1613-1622. doi: 10.1038/s41436-020-0867-5.

Perrine Pennamen ¹ ², Linh Le ³ ⁴ ⁵, Angèle Tingaud-Sequeira ¹, Mathieu Fiore ⁶ ⁷, Anne Bauters ⁸, Nguyen Van Duong Béatrice ⁹, Valentine Coste ¹⁰, Jean-Claude Bordet ¹¹, Claudio Plaisant ², Modibo Diallo ¹, Vincent Michaud ², Aurélien Trimouille ¹ ², Didier Lacombe ¹ ², Eulalie Lasseaux ², Cédric Delevoye ¹² ¹³, Fanny Morice Picard ¹⁴, Bruno Delobel ¹⁵, Michael S Marks ³ ⁴, Benoit Arveiler ¹⁶ ¹⁷

Affiliations

1 Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France.
2 Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France.
3 Dept. of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.
4 Department of Pathology, Laboratory Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5 Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
6 Laboratoire d'Hématologie, CHU de Bordeaux, Bordeaux, France.
7 Reference Center for Platelet Disorders, CHU de Bordeaux, Pessac, France.
8 Hémostase et Transfusion CHU Lille, Lille, France.
9 Service d'Ophtalmologie Pédiatrique, Hôpital Saint-Vincent de Paul, Lille, France.
10 Service d'Ophtalmologie, CHU de Bordeaux, Bordeaux, France.
11 Laboratoire d'Hématologie, CHU Lyon, Lyon, France.
12 Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, France.
13 Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, France.
14 Service de Dermatologie, CHU de Bordeaux, Bordeaux, France.
15 Centre de Génétique Chromosomique, GHICL, Hôpital Saint Vincent de Paul, Lille, France.
16 Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France. benoit.arveiler@chu-bordeaux.fr.
17 Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France. benoit.arveiler@chu-bordeaux.fr.

PMID: 32565547 DOI: 10.1038/s41436-020-0867-5

Abstract

Purpose: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive bleeding, and often additional symptoms. Variants in ten different genes have been involved in HPS. However, some patients lack variants in these genes. We aimed to identify new genes involved in nonsyndromic or syndromic forms of albinism.

Methods: Two hundred thirty albinism patients lacking a molecular diagnosis of albinism were screened for pathogenic variants in candidate genes with known links to pigmentation or HPS pathophysiology.

Results: We identified two unrelated patients with distinct homozygous variants of the BLOC1S5 gene. Patients had mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5^-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele.

Conclusion: Mutation of BLOC1S5 is disease-causing, and we propose that BLOC1S5 is the gene for a new form of Hermansky-Pudlak syndrome, HPS-11.

Keywords

BLOC-1; BLOC1S5; Hermansky–Pudlak syndrome; albinism; pathogenic variant.

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