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

Joshi StephenTadafumi YokoyamaNathanial J TolmanKevin J O'BrienElena-Raluca NicoliBrian P BrooksLaryssa HurynSteven A TitusDavid R AdamsDong ChenWilliam A GahlBernadette R GochuicoMay Christine V Malicdan
Published in: PloS one (2017)
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.
Keyphrases
  • case report
  • pulmonary fibrosis
  • induced apoptosis
  • atrial fibrillation
  • cell death
  • genome wide
  • single molecule
  • quantum dots
  • signaling pathway
  • drug induced
  • case control