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.
Highlights
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
On the premises that the eye is the embryonic extension of the brain[21] and ocular albinism has been associated to neurodevelopmental disorders[22,23], we focused our research on the effects of dysbindin-1 deletion in the retina, by using Dys−/− mice as a novel animal model of Hermansky-Pudlak syndromes (HPS)-7
Dysbindin mutations have been associated to a rare disease, named Hermansky-Pudlak syndrome 7 (HPS-7), characterized by pulmonary fibrosis, abnormalities in platelet aggregation and oculocutaneous albinism, which alters retinal functions[13]
Summary
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. Dysbindin-1 is 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]. 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]. I.e. decreased ERG response was found in patients with HPS syndromes[12] and ocular albinism[13]. Several mutations at DTNBP1 have been associated with human
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