Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5

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 Organell...

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Bibliographic Details
Published in:PloS one 2017-03, Vol.12 (3), p.e0173682-e0173682
Main Authors: Stephen, Joshi, Yokoyama, Tadafumi, Tolman, Nathanial J, O'Brien, Kevin J, Nicoli, Elena-Raluca, Brooks, Brian P, Huryn, Laryssa, Titus, Steven A, Adams, David R, Chen, Dong, Gahl, William A, Gochuico, Bernadette R, Malicdan, May Christine V
Format: Article
Language:English
Subjects:
Acidification
Albinism
Biology and Life Sciences
Biosynthesis
Bleeding
Compartments
Defects
Disease
Evolution
Fibroblasts
Fibrosis
Genes
Genetic disorders
Genetics
Genomes
Health aspects
Hermanski-Pudlak Syndrome - genetics
Hermanski-Pudlak Syndrome - pathology
Hermansky-Pudlak syndrome
Humans
Insertion
Lung diseases
Medicine and Health Sciences
Mutation
Nucleotides
Oculocutaneous albinism
Organelles
Patients
Pediatrics
Proteins
Pulmonary fibrosis
Research and Analysis Methods
Skin
Transcription
Tyrosinase
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0173682