Oral communication, CS23 / C114

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

BLOC-1 mutation screening in Hermansky-Pudlak Syndrome reveals a new HPS subtype, HPS-9, associated with mutations in PLDN(pallidin) and a novel BLOS3 (HPS-8) mutation.

BACKGROUND: Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive condition characterized by oculocutaneous albinism and a bleeding diathesis due to absent platelet delta granules. HPS, a genetically heterogeneous disorder of intracellular vesicle biogenesis, and has 8 known subtypes, 7 of which are associated with genes encoding different Biogenesis of Lysosome-related Organelles Complex (BLOC) proteins. METHODS: We screened patients with HPS-like symptoms for mutations in HPS1-6 and found no functional mutations in 38 individuals. We then examined these individuals for all 8 genes encoding the BLOC-1 proteins. RESULTS: We identified homozygous nonsense mutations in PLDN, encoding the BLOC-1 subunit, pallidin, in a single individual with characteristic features of HPS. No PLDN mutations have previously been described in humans, although Pldn is mutated in the HPS mouse model pallid. The pallidin protein interacts with the early endosomal t-SNARE syntaxin-13. We could not detect any full-length pallidin protein in our HPS-9 patient's fibroblasts or melanocytes despite normal mRNA expression of the mutant transcript. An alternative transcript was detected in the patient that would skip the exon that harbors the mutation; however, we demonstrate that, if this transcript were translated into protein, it would not interact with syntaxin-13 although it correctly localizes to early endosomes. We also identified only the second mutation to date in BLOS3, causing HPS-8. In this infant's melanocytes, BLOS3 mRNA expression was significantly reduced compared to control, suggesting nonsense-mediated decay was occurring for this mutation. Absence of either PLDN or BLOS3 causes instability of the BLOC-1 protein complex, and in both HPS-9 and HPS-8 melanocytes, the melanogenic protein TYRP1 showed aberrant localization, increased plasma-membrane trafficking, and failure to reach melanosomes. CONCLUSION: These results help explain the patients' severe albinism and establish a common cellular defect within patients having BLOC-1 gene mutations.

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