DNA polymerase gamma (pol gamma ) is required to maintain the genetic integrity of the 16,569-bp human mitochondrial genome (mtDNA). Mutation of the nuclear gene for the catalytic subunit of pol gamma (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA. We describe a heterozygous dominant mutation (c.1352G-->A/p.G451E) in POLG2, the gene encoding the p55 accessory subunit of pol gamma , that causes progressive external ophthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase (COX)-deficient muscle fibers. Biochemical characterization of purified, recombinant G451E-substituted p55 protein in vitro revealed incomplete stimulation of the catalytic subunit due to compromised subunit interaction. Although G451E p55 retains a wild-type ability to bind DNA, it fails to enhance the DNA-binding strength of the p140-p55 complex. In vivo, the disease most likely arises through haplotype insufficiency or heterodimerization of the mutated and wild-type proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype.

Aims To compare the ocular trauma score (OTS) and the classification and regression tree (CART) as prognostic models of visual outcome after open globe injury. Methods A retrospective review of 100 consecutive open globe injuries at the Sunderland Eye Infirmary was conducted from January 1999 to December 2007. Univariate chi-square analysis was used to identify the variables associated with visual outcome. We compared the CART and OTS predictions with the actual visual outcomes and calculated the sensitivity and specificity of each model. Results The variables most predictive of visual loss were an RAPD, poor initial vision, lid laceration, posterior wound, and globe rupture. The sensitivity to predict visual survival (LP or better) was 97.4% for OTS and 93.5% for CART. The specificity to predict no vision (NPL or enucleation) was 100% for OTS and 73.9% for CART. The sensitivity to predict minimal-to-severe visual loss (3/60 or better) was 90.9% for OTS and 85.7% for CART. The specificity to predict profound visual loss (worse than 3/60) was 100% for OTS and 81.8% for CART. Conclusions We identified several factors that can help in deciding on the prognostic value of primary globe repair. Both the OTS and CART had high predictive accuracy, but the OTS had higher prognostic accuracy and could be used in counselling patients and in management decision-making.

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The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues.