Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG b-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision.
The novel profile identified in this study suggests the existence of more than two rod pathways. The distinctive ERG feature was not observed in patients with X-linked CSNB1 and additional affected individuals with unknown molecular defect. These observations will help to discriminate autosomal recessive from X-linked recessive cases by ERG and molecular genetic analysis.
An abnormal pre- or perinatal medical history is the most important risk factor for CVI in children, and therefore in deciding which children should be referred for further multidisciplinary assessment. Additional symptoms of cerebral damage, i.e., cerebral palsy, visual field defects, partial optic atrophy, and a CR ≥2 may support the diagnosis. CVI questionnaires should not be used for screening purposes as they yield too many false positives.
ABSTRACT.Purpose: Causes of low vision in the Netherlands may have changed over time. The purpose of this study is to assess trends over the last two decades. Methods: Socio-demographic and medical data, including ophthalmic diagnosis and inheritance patterns for 2843 children with low vision (0-21 years; 50% representation) referred to a Dutch institute for low vision (Bartime´us) over a 21-year period between 1988 and 2009, were included in the analysis. For the 19 most common diagnoses, inheritance and presence of mental impairment, trend analyses were performed with logistic regression models; odds ratios (OR) for a 10-year time span were reported. Results: Cerebral visual impairment (CVI) was found in 27.2% (97% mental impairment), albinism in 8.0%. Over time, nystagmus (6.6%; OR = 1.42), retinitis pigmentosa (2.9%; OR = 1.61), cone-rod dystrophy (2.6%; OR = 1.98) and hyperopia (2.0%; OR = 3.66) increased significantly. Cataract (4.9%; OR = 0.64), aniridia (1.6%; OR = 0.42) and retinopathy of prematurity (ROP; 2.0%; OR = 0.45) decreased significantly. There was a significant increase in genetic disorders (41.0%; OR = 1.49) and in co-occurrence of mental impairment (52.2% OR = 1.16). Conclusion: In the last two decades, treatable or preventable disorders (such as cataract and ROP) have become a less common cause of low vision in children. However, the prevalence of complex (genetic) and untreatable disorders (CVI) has taken its place, as a result of increased survival of preterm and low birth weight children and improved diagnostic possibilities. Knowledge of the prevalence of low vision, its causes and trends over time may help policy makers to define effective intervention strategies and to monitor its impact.
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