Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice

Juvenile Batten disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy

PURPOSE To characterize the retinal phenotype of juvenile neuronal ceroid lipofuscinosis (JNCL), highlight delayed and mistaken diagnosis, and propose an algorithm for early identification. DESIGN Retrospective case series. SUBJECTS Eight children (5 females) with JNCL. METHODS Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and both microscopy and molecular genetic testing. MAIN OUTCOME MEASUREMENTS Demographic data, signs and symptoms, visual acuity, FAF and OCT findings, ERG phenotype, and microscopy/molecular genetics. RESULTS Subjects presented with rapid bilateral vision loss over one to eighteen months, with mean visual acuity deteriorating from 0.44 LogMAR (range: 0.20 - 1.78 LogMAR) at baseline, to 1.34 LogMAR (0.30 LogMAR - light perception) at last follow-up. Age of onset ranged from 3 to 7 years (mean 5.3 years). The age at diagnosis of JNCL ranged from 7 to 10 years (mean 8.3 years). Six children displayed eccentric fixation, and six had cognitive or neurological signs at time of diagnosis (75%). Seven patients had bilateral bull’s-eye maculopathy at presentation. Coats-like exudative vasculopathy, not previously reported in JNCL, was observed in one patient. OCT imaging revealed near complete loss of outer retinal layers, and marked atrophy of the nerve fibre and ganglion cell layers, at the central macula. An ‘electronegative’ ERG was present in four patients (50%), but with additional a-wave reduction; there was an undetectable ERG in the remaining four. Blood film microscopy revealed vacuolated lymphocytes and electron microscopy showed lysosomal (fingerprint) inclusions, in all eight patients. CONCLUSIONS In a young child with bilateral rapidly progressive vision loss and macular disturbance, blood film microscopy to detect vacuolated lymphocytes is a rapid, readily accessible, and sensitive screening test for JNCL. Early suspicion of JNCL can be aided by detailed directed history and high-resolution retinal imaging, with subsequent targeted microscopy/genetic testing. Early diagnosis is critical to ensure appropriate management, counselling, support and social care for children and their families. Furthermore, although potential therapies for this group of disorders are in early phase clinical trial, realistic expectations are that successful intervention will be most effective when initiated at the earliest stage of disease

Crops that feed the world 9. Oats- a cereal crop for human and livestock feed with industrial applications

Oats are a low input cereal widely grown across the world as both a grain and forage crop. Significant areas of production are in Northern Europe and North America and also in China and Australia. Although a traditional crop in many countries, in the last 50 years there has been a significant shift in oat production as a consequence of changing agricultural production and competition from other cereal crops. Oats are of significant economic importance for human consumption, for livestock feed and increasingly as a source of high value compounds with industrial applications as a consequence of the many unique properties of the oat grain. Traditional use in human diets in many countries has been boosted by the recent recognition of oats as a health food. This is attributed to the presence of β-glucan, the major endospermic cell wall polysaccharide. As a result, there has been an increase in the use of oats and a broadening of oat based products. Increasing knowledge of the composition of the oat grain and its value for the various end-users is leading to new opportunities for the crop. While the value of oats as a break crop in cereal based rotations is widely recognised, maintaining the profitability of the crop whilst meeting the needs of end users is essential for future production. Opportunities exist for plant breeders and agronomists to introduce new oat varieties with tailored agronomic approaches to address this challenge and to ensure the sustainability of oats for the future