Retinal biomarkers and pharmacological targets for Hermansky-Pudlak syndrome 7

Abstract

Deletion of dystrobrevin binding protein 1 has been linked to Hermansky-Pudlak syndrome type 7 (HPS-7), a rare disease characterized by oculocutaneous albinism and retinal dysfunction. We studied dysbindin-1 null mutant mice (Dys −/− ) to shed light on retinal neurodevelopment defects in HPS-7. We analyzed the expression of a focused set of miRNAs in retina of wild type (WT), Dys +/− and Dys −/− mice. We also investigated the retinal function of these mice through electroretinography (ERG). We found that miR-101-3p, miR-137, miR-186-5p, miR-326, miR-382-5p and miR-876-5p were up-regulated in Dys −/− mice retina. Dys −/− mice showed significant increased b-wave in ERG, compared to WT mice. Bioinformatic analysis highlighted that dysregulated miRNAs target synaptic plasticity and dopaminergic signaling pathways, affecting retinal functions of Dys −/− mice. Overall, the data indicate potential mechanisms in retinal neurodevelopment of Dys −/− mice, which may have translational significance in HSP-7 patients, both in terms of diagnostic/prognostic biomarkers and novel pharmacological targets.Dystrobrevin binding protein 1 gene (DTNBP1) encodes dysbindin-1, a ubiquitous protein that regulates membrane localization of synaptic proteins, through the regulation of synaptic vesicles and receptors recycling 1,2 . Dysbindin-1 is widely expressed in the brain, both in neurons and glial cells 1,3-5 . Dysbindin-1 is also expressed in the eye 6 and mutations leading to DTNBP1 deletion have been associated with the subtype 7 of Hermansky-Pudlak syndrome (HPS-7) 7,8 .Hermansky-Pudlak syndromes (HPS) are heterogeneous genetic disorders characterized by pulmonary fibrosis, abnormalities in platelet aggregation and oculocutaneous albinism 7,8 . Pulmonary fibrosis is the most serious complication of HPS, which cannot be effectively treated with steroids or pirfenidone, when insufficient residual lung function occurs 9 .The zebrafish fade out (fad) locus mutant has been reported as lower vertebrate model of HSP with retinal morphology and function characterization 10 . Recently, DTNBP1 knock-out mice (Dys −/− ) showed ocular albinism related to a drop out of melanosomes in retinal pigmented epithelium and choroid, compared to wild type mice (WT) 11 . Additionally, retinal melanosomes in Dys −/− mice were found to have irregular shape and small dimensions 7 .Retinal function has not yet been evaluated in Dys −/− mice. Visual dysfunction, i.e. decreased ERG response was found in patients with HPS syndromes 12 and ocular albinism 13 . Interestingly, visual dysfunctions have also been found in schizophrenic patients and individuals bearing dysbindin mutations, associated with increased risk of schizophrenia development 6,14 . Furthermore, several mutations at DTNBP1 have been associated with human intelligence [15][16][17][18] , and cognitive responses to antipsychotics in animal models and patients with schizophrenia 19,20 . Dysregulation of dysbindin-1 expression and function, related to gene mutation, have detrimental effects on neurod...

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