Ratnapriya R.,U.S. National Institutes of Health |
Zhan X.,University of Michigan |
Fariss R.N.,U.S. National Institutes of Health |
Branham K.E.,University of Michigan |
And 65 more authors.
Human Molecular Genetics | Year: 2014
Neurodegenerative diseases affecting the macula constitute amajor cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial lateonset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominantmaculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-richextracellular matrix (ECM). Sangersequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch'smembrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR 5 1.10; P-value 5 3.79 3× 10-5). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes. © The Author 2014.
Aguila M.,UCLInstitute of Ophthalmology |
Bevilacqua D.,UCLInstitute of Ophthalmology |
Mcculley C.,UCLInstitute of Ophthalmology |
Schwarz N.,UCLInstitute of Ophthalmology |
And 11 more authors.
Human Molecular Genetics | Year: 2014
The molecular chaper one Hsp90 is important for the functional maturation of many client proteins, and in hibitors are in clinical trials for multiple indications incancer. Hsp90 inhibition activates the heat shock response and can improve viability in a cell model of the P23H misfolding mutation in rhodopsin that causes autosomal dominant retinitis pigmentosa (adRP). Here, we show that a single low doseof the Hsp90 inhibitor HSP990 enhanced visual function and delayed photoreceptor degeneration in a P23H transgenic rat model. This was associated with the induction of heat shock protein expression and reduced rhodopsin aggregation. We then investigated the effect of Hsp90 inhibition on a different type of rod opsin mutant, R135L, which is hyperphosphorylated, binds arrest in and disrupts vesicular traffic. Hsp90 inhibition with17-AAG reduced the intracellular accumulation of R135L and abolished arrestin binding in cells. Hsf-1-/- cells revealed that the effect of 17-AAG on P23H aggregation was dependent on HSF-1, whereas the effect on R135L was HSF-1 independent. Instead, the effect on R135L was mediated by a requirement of Hsp90 for rhodopsin kinase (GRK1) maturation and function. Importantly, Hsp90 inhibition restored R135L rod opsin localization to wild-type (WT) phenotype in vivo in rat retina. Prolonged Hsp90 inhibition with HSP990 in vivo led to a posttranslational reduction in GRK1 and phosphodiesterase (PDE6) protein levels, identifying them as Hsp90 clients. These data suggest that Hsp90 represents a potential therapeutic target for different types of rhodopsin adRP through distinct mechanisms, but also indicate that sustained Hsp90 inhibition might adversely affect visual function.© The Author 2013. Published by Oxford University Press.