Congenital stationary night blindness: An analysis and update of genotype–phenotype correlations and pathogenic mechanisms
Introduction
Congenital stationary night blindness (CSNB) refers to a genetically determined largely non-progressive group of retinal disorders that predominantly affect signal processing within photoreceptors, retinoid recycling in the retinal pigment epithelium (RPE) or signal transmission via retinal bipolar cells (Zeitz, 2007). CSNB is clinically and genetically heterogeneous. Patients often complain of night or dim light vision disturbance or delayed dark adaptation, but photophobia is also reported in a subgroup of patients. Some forms may be associated with other ocular signs such as poor visual acuity, myopia, nystagmus, strabismus and fundus abnormalities (Zeitz, 2007). The night vision disturbance may be overlooked since it is highly subjective especially for individuals living in an urban or well-lit environment. Vision problems may also be denied (Dryja, 2000). Scotopic vision is rarely tested routinely and CSNB is likely under-diagnosed by clinicians, confounding estimates of prevalence.
To our knowledge, the first individuals diagnosed with CSNB were the descendants of Jean Nougaret, who was born 1637 in southern France. Since then many clinicians and researchers have contributed to the understanding of different CSNB phenotypes, genetic causes and pathogenic mechanisms. The purpose of this article is to summarise these findings and to extend current knowledge by inclusion of novel data and interpretation.
Section snippets
Clinical classification
CSNB can be subdivided according to the pattern of inheritance which may be X-linked, autosomal recessive or autosomal dominant (see also: 3. CSNB genes and mutations). Fundus appearance may be normal or abnormal but in all cases the full field electroretinogram (FF-ERG) is critical for functional phenotyping and precise diagnosis.
Gene identification strategies
CSNB is a group of genetically and clinically heterogeneous retinal disorders caused by mutations in seventeen identified genes (Table 1) with an unknown number yet to be identified. Genes mutated in patients with CSNB have been identified by different methods including classical linkage analysis with a combination of candidate gene and positional cloning approaches, autozygosity mapping, pure candidate gene approaches as well as by whole exome sequencing (WES).
Classical linkage approaches have
Animal models for CSNB
Animal models have been shown to be an excellent tool to identify and to elucidate the pathogenic mechanism of gene defects underlying CSNB. In addition, well characterized animal models are crucial to develop pharmaceutical or genetic treatments. In Table 4 we summarize more than 30 animal models of CSNB. Most are mouse models, but for some gene defects other species including zebrafish, rat, dog and horse have been described. We provide the gene defect with the respective accession number if
Molecules important in the phototransduction cascade and retinoid recycling (RHO, GNAT1, PDE6B, SLC24A1, RDH5, RPE65, RLBP1, GRK1 and SAG)
Several forms of CSNB are caused by mutations that affect molecules of the phototransduction cascade or retinoid recycling and these are highlighted in Fig. 11. Rhodopsin (RHO), a seven transmembrane G-protein coupled receptor represents the light-sensitive pigment of rod photoreceptors, which consists of the 11-cis-aldehyde of vitamin A (11-cis-retinal) bound covalently to opsin. Upon absorption of a photon by the rods, the chromophore is converted to its all-trans isomer and subsequently RHO
Summary and future perspectives
An important first step in the genetic investigation of CSNB is comprehensive phenotyping. Phenotypic characterisation may suggest genes that encode pre- or postsynaptic proteins to be good candidates (Fig. 11, Fig. 14). A “Riggs-type” ERG (marked scotopic ERG a-wave reduction; see Section 2.2.1) may prompt investigation of molecules and novel mutations that affect phototransduction or retinoid recycling whereas an electronegative (“Schubert-Bornshein-type”) ERG (scotopic ERG a-wave normal and
CSNB consortium
Tharigopala Arokiasamy, Mario Anastasi, Claire Audier, Eyal Banin, Wolfgang Berger, Elfride De Baere, Shomi S. Bhattacharya, Rebecca Bellone, Béatrice Bocquet, Dominique Bonneau, Kinga Bujakowska, Ingele Casteels, Sabine Defoort-Dhellemmes, Miguel Dias, Hélène Dollfus, Isabelle Drumare, Said El Shamieh, Christoph Friedburg, Irene Gottlob, Cyril Goudet, Christian P. Hamel, John R. Heckenlively, Elise Héon, Graham E Holder, Samuel G. Jacobson, Bernhard Jurklies, Josseline Kaplan, Ulrich Kellner,
Acknowledgments
We are thankful to all patients and family members who participated in this study. We acknowledge assistant engineers from CZ's previous laboratory at the Institute for Medical Genetics and Gene Diagnostics from the University in Zurich, Switzerland including Ursula Forster, Silke Feil and Mariana Wittmer and from the current laboratory at the Institut de la Vision in Paris, France including Marie-Elise Lancelot, Christelle Michiels, Vanessa Démontant, Christel Condroyer and Aline Antonio for
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Percentage of work contributed by each author in the production of the manuscript is as follows: Christina Zeitz: 70%; Anthony G. Robson: 10%; Isabelle Audo: 20%.