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.

Lessons of a day hospital: Comprehensive assessment of patients with albinism in a European setting

“…Overall, the five HPS patients had similar phenotypes. The patients with HPS‐5 only had slight systemic symptoms (frequent ecchymoses, episodic abdominal pain) showing a mild phenotype compared to HPS‐1, as recently described in literature (Huizing et al., ; Korswagen, Huizing, Simsek, Janssen, & Zweegman, ; Michaud et al., ; Ringeisen, Schimmenti, White, Schoonveld, & Summers, ; Stephen et al., ). The patient with HPS‐6 had frequent bruises, bleedings and dyspnoea on exertion.…”

Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant

“…Fibroblasts were cultured from a forearm skin biopsy as described (Stephen, 2017). Dermal fibroblasts from two healthy volunteers served as normal controls; dermal fibroblasts from 3 adults with HPS-1 served as BLOC-3 complex controls.…”

“…Results were normalized with expression of RFLP13a (Thermo Fisher) and analyzed. Western blot analysis was performed as described (Stephen, 2017). Membranes were incubated overnight at 4°C with rabbit monoclonal anti-HPS1 antibody (Abcam, Cambridge, UK), rabbit polyclonal anti-HPS4 antibody (Santa Cruz Biotechnology Inc., Dallas TX), rabbit polyclonal anti-HPS6 antibody (Origene Technologies Inc., Rockville, MD), or mouse monoclonal anti-β-actin antibody (Sigma-Aldrich, St. Louis, MO).…”

Clinico‐molecular analysis of eleven patients with Hermansky–Pudlak type 5 syndrome, a mild form of HPS

“…Patients with HPS‐5 previously reported in the literature are listed in Table (Khan, Tamimi, Lenzner, & Bolz, ; Korswagen, Huizing, Simsek, Janssen, & Zweegman, ; Nazarian et al., ; Stephen et al., ; Wei et al., ). Nine patients have brown hair, and for only six, a mild depigmentation of the skin was noted.…”