SUMMARY Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk-variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene P16/INK4A (cyclin-dependent kinase inhibitor 2A). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in P16/INK4A expression with a subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing P16/INK4A expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.

The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.

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Purpose To determine the genetic basis of early onset autosomal recessive Best vitelliform macular dystrophy (arBVMD) in a family with three affected children. Design Clinical and family-based genetic study. Methods Seven subjects making up a family with three children affected by Best vitelliform macular dystrophy were studied. Standard ophthalmic exam with dilated ophthalmoscopy and imaging were performed in each individual. The eleven exons of BEST1 were directly sequenced. Results All three affected children have the clinical characteristic features of Best vitelliform macular dystrophy: large macular vitelliform lesions, scattered vitelliform lesions along the arcades and in the peripheral retina, and an accumulation of serous retinal fluid. A novel compound heterozygous mutation in the BEST1 gene was found in the three affected individuals (L41P and I201T). The unaffected parents and children only harbor one heterozygous mutation. Conclusion arBVMD can be caused by the compound heterozygous mutation L41P and I201T in the BEST1 gene.

Ovarian cancer, a leading cause of death in women, typically spreads locally and rarely metastasizes to the brain or seeds the leptomeninges. We present a case of a 62-year-old woman with a history of treated ovarian cell carcinoma who developed bilateral sensorineural deafness and right-sided facial weakness and on imaging was found to have bilateral internal auditory canal (IAC) masses and leptomeningeal carcinomatosis, pathologically proven by cerebrospinal fluid cytology. We discuss her magnetic resonance imaging and positron emission tomography-computed tomography findings and review the imaging characteristics of IAC metastases. Finally, we review the literature on leptomeningeal carcinomatosis from ovarian cancer and discuss the high incidence of bilateral IAC metastases in patients with leptomeningeal carcinomatosis.