The long dystrophin gene product Dp427 modulates retinal function and vascular morphology in response to age and retinal ischemia

Abstract

Mutations in dystrophin are the major cause of muscular dystrophies. Continuous muscular degeneration and late stage complications, including cardiomyopathy and respiratory insufficiency, dominate the clinical phenotype. Gene expression and regulation of the dystrophin gene outside of muscular tissue is far more complex. Multiple tissue-specific dystrophin gene products are widely expressed throughout the body, including the central nervous system and eye, predisposing affected patients to secondary complications in non-muscular tissues. In this study, we evaluated the impact of the full-length dystrophin gene product, Dp427, on retinal homeostasis and angiogenesis. Based on the clinical case of a Duchenne muscular dystrophy (DMD) patient who developed severe fibrovascular changes in the retina in response to hypoxic stress, we hypothesized that defects in Dp427 make the retina more susceptible to stresses such as ageing and ischemia. To further study this, a mouse strain lacking Dp427 expression (Mdx) was studied during retinal development, ageing and in the oxygen-induced retinopathy (OIR) model. While retinal vascular morphology was normal during development and ageing, retinal function measured by electroretinography (ERG) was slightly reduced in young adult Mdx mice and deteriorated with age. Mdx mice also had increased retinal neovascularization in response to OIR and more pronounced long-term deterioration in retinal function following OIR. Based on these results, we suggest that DMD patients with a mutation in Dp427 may experience disturbed retinal homeostasis with increasing age and therefore be prone to develop excessive retinal neovascular changes in response to hypoxic stress. DMD patients in late disease stages should, thus, be regularly examined to detect asymptomatic retinal abnormalities and prevent visual impairment.

Keywords: Angiogenesis; Dp427; Duchenne muscular dystrophy; Electroretinography; Hypoxia; Oxygen-induced retinopathy; Proliferative retinopathy.