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

<div><p>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 <i>HPS5</i> 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.</p></div

Clinical characteristics of the patient.

<p><b>(A)</b> Photograph showing skin and hair color of the patient (<b>B)</b> Iris transillumination: 1, normal right iris; patient’s iris with transillumination defects (2, right eye; 3, left eye); Fundus: 4, normal fundus right eye; patient’s poorly pigmented fundi with peripapillary atrophy and foveal hypoplasia (5, right eye; 6, left eye) <b>(C)</b> Electron microscopy (EM) findings of the thin sections of platelets imaged by transmission EM, showing platelet from control (left panel) and patient (right panel) <b>(D)</b> whole mount EM of platelets showing lack of delta-granules in patient (right panel) compared to control (left panel) <b>(E)</b> Computed tomography scan of the chest shows no evidence of pulmonary fibrosis (left panel); right panel showing foamy appearance of alveolar macrophages in bronchoalveolar lavage fluid.</p

Molecular and expression analysis.

<p>(A) Chromatogram showing intronic mutation (c.285-10A>G) in genomic level (upper panel) and cDNA level (middle panel) of the patient. Lower panel shows normal cDNA sequence from control for comparison with patient. (B) Relative quantification of mRNA expression (three different isoforms) in patient derived dermal fibroblasts, compared to control. Error bar represents standard deviation from triplicates (*: p<0.05, **: p<0.01). (C) Western blotting results showing the expression of HPS5 in patients compared to control. Two different controls (Control-1 and Control-2), two additional patients with HPS5 (HPS5-1 and HPS5-2), and our proband were included. The level of protein expression was normalized with β-actin.</p

<i>HPS5</i> mutations reported in the literature.

<p><i>HPS5</i> mutations reported in the literature.</p