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Falk M.J.,Children's Hospital of Philadelphia | Zhang Q.,Massachusetts Eye and Ear Infirmary | Nakamaru-Ogiso E.,University of Pennsylvania | Kannabiran C.,LV Prasad Eye Institute LVPEI | And 42 more authors.
Nature Genetics | Year: 2012

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss. Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis. Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA. © 2012 Nature America, Inc. All rights reserved.

Garland D.L.,Massachusetts Eye and Ear Infirmary | Fernandez-Godino R.,Massachusetts Eye and Ear Infirmary | Kaur I.,LV Prasad Eye Institute LVPEI | Speicher K.D.,Wistar Institute | And 4 more authors.
Human Molecular Genetics | Year: 2014

Macular degenerations, inherited and age related, are important causes of vision loss. Human genetic studies have suggested perturbation of the complement system is important in the pathogenesis of age-related macular degeneration. The mechanisms underlying the involvement of the complement system are not understood, although complement and inflammation have been implicated in drusen formation. Drusen are an early clinical hallmark of inherited and age-related forms of macular degeneration. We studied one of the earliest stages of macular degeneration which precedes and leads to the formation of drusen, i.e. the formation of basal deposits. The studies were done using a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by a p.Arg345Trp mutation in EFEMP1. The hallmark of DHRD/ML is the formation of drusen at an early age, and gene targeted Efemp1R345W/R345W mice develop extensive basal deposits. Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1R345W/R345W mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts. The proteomic analyses also identified significant changes in proteins with immune-related function, including complement components, in the diseased tissue samples. Genetic ablation of thecomplementresponsevia generation ofEfemp1R345W/R345W:C3-/- double-mutantmice inhibited the formation of basal deposits. The results demonstrate a critical role for the complement system in basal deposit formation, and suggest that complement-mediated recognition of abnormal ECM may participate in basal deposit formation in DHRD/ML and perhaps other macular degenerations. © The Author 2013. Published by Oxford University Press. All rights reserved.

Sefat F.,Kroto Research Institute | McKean R.,Rutherford Appleton Laboratory | Deshpande P.,Kroto Research Institute | Ramachandran C.,LV Prasad Eye Institute LVPEI | And 4 more authors.
Procedia Engineering | Year: 2013

Our aim was to produce, sterilize and store a synthetic, rapidly biodegrading membrane for cultured limbal stem cell transplantation. Membranes were electrospun from Poly(D, L-lactide-co-glycolide) with a 50:50 ratio of lactide and glycolide comparing 44 kg/mol and 153 kg/mol molecular weights (MW) and sterilized with y-irradiation and stored for up to a year at a range of temperatures. Cells attached well on both MW membranes. The lower MW degraded faster than the higher MW membranes. y-irradiation accelerated membrane breakdown when wet but sterilised membranes could be stored dry for at least a year at -20°C. © 2013 The Authors.

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