No abstract

Summary Hermansky–Pudlak syndrome (HPS) is an autosomal recessive and genetically heterogeneous disorder characterized by oculocutaneous albinism, bleeding tendency, and ceroid deposition, which likely leads to deleterious lesions in lungs, heart, and other organs. Currently, nine genes have been identified as causative for HPS in humans. Their pathological effects are attributable to the disrupted biogenesis of lysosome‐related organelles (LROs) existing in multiple cell types or tissues, causing the pigmentory and non‐pigmentory defects. This review focuses on the functional aspects of HPS genes in regulating LRO biogenesis and signal transduction. The understanding of these mechanisms expands our knowledge about the involvement of lysosomal trafficking in the targeting of cargoes for constitutive transport, degradation, and secretion. This opens an avenue to the pathogenesis of lysosomal trafficking disorders at the cellular and developmental levels.

Connexins and pannexins are two protein families that play an important role in cellular communication. Pannexin 1 (PANX1), one of the members of pannexin family, is a channel protein. It is glycosylated and forms three species, GLY0, GLY1, and GLY2. Here, we describe four independent families in which mutations in PANX1 cause familial or sporadic female infertility via a phenotype that we term “oocyte death.” The mutations, which are associated with oocyte death, alter the PANX1 glycosylation pattern, influence the subcellular localization of PANX1 in cultured cells, and result in aberrant PANX1 channel activity, ATP release in oocytes, and mutant PANX1 GLY1. Overexpression of a patient-derived mutation in mice causes infertility, recapitulating the human oocyte death phenotype. Our findings demonstrate the critical role of PANX1 in human oocyte development, provide a genetic explanation for a subtype of infertility, and suggest a potential target for therapeutic intervention for this disease.