title: Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5.
abstract: Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Nathanial J
authors.initials: NJ
authors.lastname: Tolman
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: O'Brien
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Elena-Raluca
authors.initials: ER
authors.lastname: Nicoli
authors.affiliation: Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
authors.affiliation: Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Laryssa
authors.initials: L
authors.lastname: Huryn
authors.affiliation: Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Titus
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: May Christine V
authors.identifier: http://orcid.org/0000-0003-1697-6959
authors.initials: MC
authors.lastname: Malicdan
mesh_terms: D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000473:pathology*; D006801:Humans; D009154:Mutation