ArticleExperimental eye research2016
Mthfr as a modifier of the retinal phenotype of Crb1(rd8/rd8) mice.
Article in Experimental eye research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- Characterization of a spontaneous microphthalmia-like mutant mouse with isolated ocular defects.PloS one · 2026Article
- Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina.Life science alliance · 2024Article
- Diverse functions and pathogenetic role of Crumbs in retinopathy.Cell communication and signaling : CCS · 2024Review
- Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model.PLoS genetics · 2022Article
- Plasma homocysteine and macular thickness in older adults-the Rugao Longevity and Aging Study.Eye (London, England) · 2022Article
- Consanguinity-based analysis of exome sequencing yields likely genetic causes in patients with inherited retinal dystrophy.Orphanet journal of rare diseases · 2021Article
- Hyperhomocysteinemia-induced death of retinal ganglion cells: The role of Müller glial cells and NRF2.Redox biology · 2019Article
- Detailed electroretinographic findings in rd8 mice.Documenta ophthalmologica. Advances in ophthalmology · 2017Article
- Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration.Mammalian genome : official journal of the International Mammalian Genome Society · 2016Article
- Retinal Dystrophies and the Road to Treatment: Clinical Requirements and Considerations.Asia-Pacific journal of ophthalmology (Philadelphia, Pa.)Review
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6 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations in crumb homologue 1 (CRB1) in humans are associated with Leber's congenital amaurosis (LCA) and retinitis pigmentosa (RP). There is no clear genotype-phenotype correlation for human CRB1 mutations in RP and LCA. The high variability in clinical features observed in CRB1 mutations suggests that environmental factors or genetic modifiers influence severity of CRB1 related retinopathies. Retinal degeneration 8 (rd8) is a spontaneous mutation in the Crb1 gene (Crb1(rdr/rd8)). Crb1(rdr/rd8) mice present with focal disruption in the outer retina manifesting as white spots on fundus examination. Mild retinal dysfunction with decreased b-wave amplitude has been reported in Crb1(rdr/rd8) mice at 18 months. Methylene tetrahydrofolate reductase (MTHFR) is a crucial enzyme of homocysteine metabolism. MTHFR mutations are prevalent in humans and are linked to a broad spectrum of disorders including cardiovascular and neurodegenerative diseases. We recently reported the retinal phenotype in Mthfr-deficient (Mthfr(+/-)) heterozygous mice. At 24 weeks the mice showed decreased RGC function, thinner nerve fiber layer, focal areas of vascular leakage and 20% fewer cells in the ganglion cell layer (GCL). Considering the variability in CRB1-related retinopathies and the high occurrence of human MTHFR mutations we evaluated whether Mthfr deficiency influences rd8 retinal phenotype. Mthfr heterozygous mice with rd8 mutations (Mthfr(+/-)(rd8/rd8)) and Crb(rd8/rd8) mice (Mthfr(+/+rd8/rd8)) mice were subjected to comprehensive retinal evaluation using ERG, fundoscopy, fluorescein angiography (FA), morphometric and retinal flat mount immunostaining analyses of isolectin-B4 at 8-54 wks. Assessment of retinal function revealed a significant decrease in the a-, b- and c-wave amplitudes in Mthfr(+/-)(rd8/rd8) mice at 52 wks. Fundoscopic evaluation demonstrated the presence of signature rd8 spots in Mthfr(+/+rd8/rd8) mice and an increase in the extent of these rd8 spots in Mthfr(+/-)(rd8/rd8) mice at 24 weeks and beyond. FA revealed marked vascular leakage, ischemia and vascular tortuosity in Mthfr(+/-)(rd8/rd8) mice at 24 and 52 weeks. Retinal dysplasia was observed in ∼14-33% Mthfr(+/-)(rd8/rd8) mice by morphometric analysis. This was accompanied by a ∼20% reduction in cells of the GCL of Mthfr(+/-)(rd8/rd8) mice at 24 and 52 weeks. Retinal flat mount immunostaining with isolectin-B4 showed neovascularization and loss of blood vessel integrity in Mthfr(+/-)(rd8/rd8) mice in contrast to mild vasculopathy in Mthfr(+/+rd8/rd8) mice. Taken together, our data support an earlier onset and worsened retinal phenotype when Mthfr and rd8 mutations coexist. Our study sets the stage for future studies to investigate the role of MTHFR deficiency in human CRB1 retinopathies.
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