A common NYX mutation in Flemish patients with X linked CSNB
ABSTRACT The Schubert-Bornschein type of complete congenital stationary night blindness (CSNB) is a genetically heterogeneous retinal disorder. It is characterised by a non-progressive disease course, often associated with high myopia and nystagmus. So far, mutations in two genes, NYX (nyctalopin) and GRM6 (metabotropic glutamate receptor 6) have been associated with this form of CSNB. The purpose of this study was to identify the genetic defect in affected male patients from Flemish families with complete CSNB.
Probands with CSNB from three large Flemish families underwent ophthalmological examination. DNA was extracted from peripheral blood, and the coding region of NYX along with parts of the 5'UTR and 3'UTR and intronic regions covering the splice sites were PCR amplified and sequenced.
In the affected individuals of three Flemish families with the complete form of CSNB a novel NYX mutation, c.855delG was identified. This deletion is predicted to lead to a frameshift mutation, p.Asp286ThrfsX62 causing a premature stop codon.
Previously, both single families with different mutations in NYX as well as different families with an identical mutation, suggestive of a founder mutation, have been described. The c.855delG deletion in NYX seems to be a common mutation associated with CSNB in the Flemish population from Belgium. Thus, we suggest performing diagnostic testing for CSNB in the Flemish population initially directed towards the identification of this mutation. Subsequent screening for other mutations in NYX or GRM6 could be performed as a second step.
Full-textDOI: · Available from: Christina Zeitz, Sep 02, 2015
- SourceAvailable from: Aaron Mercer
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- "The retina-specific ECM protein nyctalopin, derived from the NYX gene, has been implicated in a form of CSNB (Bech-Hansen et al., 2000; Pusch et al., 2000) and the mouse " no b-wave " (NYX nob ) mutant (Gregg et al., 2003, 2007). Analysis of ERGs in CSNB patients and NYX nob mutant mice indicates a failure of transmission from photoreceptors to ON bipolar cells (Khan et al., 2005; Bahadori et al., 2006; Leroy et al., 2009). This is similar to effects of postsynaptic mutations in the glutamate receptor, mGluR6, or the transduction channel, TRPM1, at the ON bipolar synapse (McCall & Gregg, 2008; Shen et al., 2009; van Genderen et al., 2009; Koike et al., 2010; Morgans et al., 2010). "
ABSTRACT: Rod and cone photoreceptors possess ribbon synapses that assist in the transmission of graded light responses to second-order bipolar and horizontal cells of the vertebrate retina. Proper functioning of the synapse requires the juxtaposition of presynaptic release sites immediately adjacent to postsynaptic receptors. In this review, we focus on the synaptic, cytoskeletal, and extracellular matrix proteins that help to organize photoreceptor ribbon synapses in the outer plexiform layer. We examine the proteins that foster the clustering of release proteins, calcium channels, and synaptic vesicles in the presynaptic terminals of photoreceptors adjacent to their postsynaptic contacts. Although many proteins interact with one another in the presynaptic terminal and synaptic cleft, these protein-protein interactions do not create a static and immutable structure. Instead, photoreceptor ribbon synapses are remarkably dynamic, exhibiting structural changes on both rapid and slow time scales.Visual Neuroscience 11/2011; 28(6):453-71. DOI:10.1017/S0952523811000356 · 1.68 Impact Factor
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- "Like mGluR6 and nyctalopin, TRPM1 is specifically enriched at dendritic tips and its elimination in mice completely abolishes ON-BC responses. Genetic association studies indicate that mutations in TRPM1 (Audo et al., 2009; van Genderen et al., 2009; Nakamura et al., 2010), mGluR6 (Zeitz et al., 2005; O'Connor et al., 2006) and nyctalopin (Bech- Hansen et al., 2000; Leroy et al., 2009) account for the majority of congenital night blindness cases in human patients. However, beyond general knowledge regarding the identity of the main players involved in ON-BC responses to light, our understanding of the mechanistic details pertaining to the organization of the signaling pathway is very limited. "
ABSTRACT: Synaptic transmission between light-sensory photoreceptor cells and downstream ON-bipolar neurons plays an important role for vertebrate vision. This process is mediated by the G-protein-coupled receptor pathway involving glutamate receptor mGluR6 and effector channel TRPM1. The signal transmission occurs on a rapid timescale; however, the molecular organization that ensures timely signaling in this cascade is unknown. Genetic studies in human patients and animal models reveal that ON-bipolar cell signaling depends on the synaptic protein nyctalopin. We have conducted a proteomic search for proteins associated with nyctalopin in the mouse retina and identified TRPM1 as the binding partner. We further demonstrate that nyctalopin additionally interacts with mGluR6 receptor. Disruption of mGluR6 prevented targeting of TRPM1 to the postsynaptic compartment of ON-bipolar neurons. These results reveal a unique macromolecular organization of the mGluR6 cascade, where principal signaling components are scaffolded by nyctalopin, creating an organization essential for the correct localization of the signaling ensemble and ultimately intact transmission of the signal at the first visual synapse.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2011; 31(32):11521-6. DOI:10.1523/JNEUROSCI.1682-11.2011 · 6.75 Impact Factor
Article: Animal Models of Retinal Disease[Show abstract] [Hide abstract]
ABSTRACT: Diseases of the retina are the leading causes of blindness in the industrialized world. The recognition that animals develop retinal diseases with similar traits to humans has led to not only a dramatic improvement in our understanding of the pathogenesis of retinal disease but also provided a means for testing possible treatment regimes and successful gene therapy trials. With the advent of genetic and molecular biological tools, the association between specific gene mutations and retinal signs has been made. Animals carrying natural mutations usually in one gene now provide well-established models for a host of inherited retinal diseases, including retinitis pigmentosa, Leber congenital amaurosis, inherited macular degeneration, and optic nerve diseases. In addition, the development of transgenic technologies has provided a means by which to study the effects of these and novel induced mutations on retinal structure and function. Despite these advances, there is a paucity of suitable animal models for complex diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, largely because these diseases are not caused by single gene defects, but involve complex genetics and/or exacerbation through environmental factors, epigenetic, or other modes of genetic influence. In this review, we outline in detail the available animal models for inherited retinal diseases and how this information has furthered our understanding of retinal diseases. We also examine how transgenic technologies have helped to develop our understanding of the role of isolated genes or pathways in complex diseases like AMD, diabetes, and glaucoma.Progress in molecular biology and translational science 01/2011; 100:211-86. DOI:10.1016/B978-0-12-384878-9.00006-6 · 3.11 Impact Factor