Perrine Pennamen1,2, Linh Le3,4,5, Angèle Tingaud-Sequeira1, Mathieu Fiore6,7, Anne Bauters8, Nguyen Van Duong Béatrice9, Valentine Coste10, Jean-Claude Bordet11, Claudio Plaisant2, Modibo Diallo1, Vincent Michaud2, Aurélien Trimouille1,2, Didier Lacombe1,2, Eulalie Lasseaux2, Cédric Delevoye12,13, Fanny Morice Picard14, Bruno Delobel15, Michael S Marks3,4, Benoit Arveiler16,17. 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.
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.
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.
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