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

• Published in: Neurochemistry international Vol. 129; p. 104489
• Main Authors: Bucher, Felicitas, Friedlander, Mollie S.H., Aguilar, Edith, Kurihara, Toshihide, Krohne, Tim U., Usui, Yoshihiko, Friedlander, Martin
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2019
• Subjects: Aging - pathology; Aging - physiology; Angiogenesis; Animals; Cell Hypoxia; Dp427; Duchenne muscular dystrophy; Dystrophin - deficiency; Dystrophin - genetics; Dystrophin - physiology; Electroretinography; Exons - genetics; Fibrosis; Gene Duplication; Humans; Hypoxia; Ischemia - pathology; Ischemia - physiopathology; Male; Mice; Muscular Dystrophy, Animal - genetics; Muscular Dystrophy, Duchenne - complications; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - pathology; Oxygen - toxicity; Oxygen-induced retinopathy; Proliferative retinopathy; Protein Isoforms - deficiency; Protein Isoforms - genetics; Protein Isoforms - physiology; Retina - diagnostic imaging; Retina - physiology; Retinal Diseases - chemically induced; Retinal Diseases - pathology; Retinal Diseases - physiopathology; Retinal Neovascularization - etiology; Retinal Neovascularization - physiopathology; Retinal Vessels - ultrastructure; Sepsis - complications; Young Adult; Electroretinography; Angiogenesis; Duchenne muscular dystrophy; Proliferative retinopathy; Hypoxia; Dp427; Oxygen-induced retinopathy
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2019.104489

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. •Older DMD patients can develop proliferative retinopathies in response to hypoxia.•In Mdx mice, lack of Dp427 leads to deterioration of visual function with age.•Mdx mice develop excessive retinal neovascular changes in OIR.•Transient hypoxia enhances long-term visual deterioration in Mdx mice.