Christina Zeitz DR2 INSERM, HDR, PhD Chemistry Life Science Neuroscience

Course and current status

Christina Zeitz is a research director (DR2) at INSERM and, together with Isabelle Audo, leads the team S6 "Identification of gene defects leading to progressive or non-progressive eye diseases" in the Department of Genetics at the Institut de la Vision (INSERM, UMR_S968, CNRS, UMR_7210, University Pierre and Marie Curie Paris6). Originally born in Germany in 1972 and studying chemistry in Freiburg, Germany, Seattle, USA and Berlin, Germany, during a student job at the Max Planck Institute of Molecular Genetics in Berlin she got the taste to work on small molecules involved in the retina. Since then she has not lost sight of retinal diseases. She obtained her PhD in Chemistry at the Free University of Berlin in 2004, which focused on the identification of a new gene involved in congenital stationary night blindness (CSNB). The laboratory work was carried out at the Max Planck Institute of Molecular Genetics in Berlin and at the Institute of Medical Genetics at the University of Zurich in Switzerland in the laboratory of Wolfgang Berger. After her thesis she continued to work in the same laboratory to identify three other genes involved in the same retinal disease. It was there, where she began to establish her first team and international collaborations to analyze genetic defects also at the functional level. Thanks to this work, she was recruited by an international committee in 2007 as a team leader at the Institut de la Vision with the recruitment at INSERM in 2010 as a CR1 and in 2015 as a DR2 researcher. The work of the team aims to identify genetic defects in large cohorts of patients with different retinal diseases by new technologies such as next generation sequencing (NGS) using large gene panels involved in these diseases or by sequencing exomes or the entire genomes. The team is also interested in studying the function of the proteins encoded by the identified genes and the pathophysiological mechanisms resulting from these gene defects. These in-depth studies lead to a better understanding of retinal physiology and pathophysiology, provide epidemiological data on the frequency of mutations identified in retinal diseases in Europe and can also identify new therapeutic targets. These studies also provide access to better clinically characterized patients, allowing for more appropriate genetic counselling as a preamble for the preparation of future clinical trials such as those involving gene therapy approaches. The other axis of her work is the development of innovative gene therapy approaches for CSNB. Together, this work delivers the prevalence of different genetic defects, identified eight other genes involved in non progressive and progressive retinal diseases and lead to the functional characterization of genes involved in CSNB, which helped to better understand signalling within the retina. This work has resulted in many original articles (eg, American Journal of Human Genetics, Progress in Retinal and Eye Research, Clinical Genetics, Orphanet Journal of Rare Diseases, BMC Human Molecular Genetics, IOVS,...) and scientific awards that Christina Zeitz received in 2006 (Pro Retina Germany and Retina Switzerland), 2012 (Dalloz Foundation Award, Institut de France pour la recherche en ophtalmologie) and PEDR INSERM 2013-2016. Christina Zeitz is a member of several scientific associations such as the Association of Research in Vision and Ophthalmology, where she was an elected member (2014-2017) for the organization of ARVO in the Biochemistry and Molecular Biology ), ASHG: The American Society of Human Genetics, GDR RCPG-PhysioMed: "G protein-coupled receptors - from physiology to drug," ISER: International Society for Eye Research, ISGEDR: International Society for Genetic Eye Diseases and Retinoblastoma, SGOF: Society of Francophone Ophthalmological Genetics. She is a guest editor for a particular issue in "Genes": "Inherited Retinal Disease: Gene Therapeutics, Genotype-Phenotype Correlations and Inheritance Models" and in "Biomed Research International": "Inherited Retinal Disease: Combining Clinical, Genetic and Biochemical Approaches for Congenital Stationary Night Blindness". Since 2016 she is a member of the editorial committee for "Orphanet Journal of Rare Diseases". She is regularly consulted as a reviewer for scientific journals, applications for grants, HDRs and theses.;

Scientific summary

The first steps in vision occur when the rod and cone photoreceptors transform light into a biochemical signal, which then gets processed through the retina. The initial processes occurring in photoreceptors, described by the phototransduction cascade, are quite well understood, while the transmission from the photoreceptors to their postsynaptic neurons remains to be dissected in more details. Knowledge about the phototransduction cascade was gained by studying retinal diseases like rod-cone or cone-rod/cone dystrophy (RCD, CRD/CD), in which molecules of this cascade are mutated. On the other hand, congenital stationary night blindness (CSNB) is a useful model to decipher the signal transmission cascade from the photoreceptors to postsynaptic neurons. RCD and CRD/CD is a clinically and genetically heterogeneous group of inherited retinal disorders usually primarily affecting rods with secondary cone degeneration or usually primarily affecting cones with secondary rod degeneration, respectively. RCD represents a progressive disorder which often starts with night blindness and leads to visual field constriction, abnormal color vision and can eventually lead to loss of central vision and complete blindness. In patients with CRD/CD initially the center vision is affected but can at later stages also lead to complete blindness. Patients with both subtypes are characterized by severely reduced to absent electroretinogram (ERG). RCD is the most common inherited form of severe retinal degeneration, with a frequency of about 1 in 4000 births and more than 1 million individuals affected worldwide. The mode of inheritance can be X-linked (5-15%), autosomal dominant (30-40%) or autosomal recessive (50-60%). The remaining patients represent isolated cases for which the inheritance trait cannot be established. Over 200 different genes and loci have been implicated in inherited retinal diseases. However, for about 60% of patients the disease causing gene defect needs to be identified ( CSNB is a retinal disorder that can be associated with night blindness and other ocular symptoms including high myopia, nystagmus and strabismus. A few CSNB cases have been described with mutations in genes coding for proteins of the phototransduction cascade. They show a so called Riggs-type of ERG with reduced a-wave and b-wave amplitudes under scotopic conditions, with mutations in RHO, PDE6B, GNAT1 and SLC24A1. However, most of the mutations implicated in CSNB are located in genes involved in retinal signaling from the photoreceptors to the adjacent bipolar cells, leading to incomplete or complete forms of CSNB. Both patient groups show a typical electrophysiological phenotype characterized by an electronegative waveform of the dark-adapted, bright-flash ERG, in which the amplitude of the b-wave is smaller than that of the a-wave. This so-called Schubert-Bornschein type of ERG response allows the discrimination of these two subtypes of CSNB. The incomplete type is characterized by both a reduced rod b-wave and substantially reduced cone response, due to both ON- and OFF- bipolar cell dysfunction, whereas the complete type is associated with a drastically reduced rod b-wave response but largely normal cone b-wave amplitudes, due to ON-bipolar cell dysfunction. We and others showed that the incomplete and the complete form of CSNB can be associated with three and five different gene defects respectively. Mutations in CACNA1F, CABP4 and CACNA2D4 lead to the incomplete form of CSNB. Mutations in NYX, GRM6, TRPM1, GPR179 and LRIT3 lead to the complete form of CSNB. To date the number of genetically unsolved cases for all CSNB patients is difficult to estimate. Our cohort (>300 patients) consists mainly of icCSNB, cCSNB and unclassified CSNB cases. Our recent work concentrated mainly on the identification of genes underlying cCSNB. For this phenotypic group, only a few patients lack mutations in the known genes indicating that most of the gene defects have been already identified. For the icCSNB group of patients, many cases of our cohort still need to be excluded for mutations in known genes. If we consider only patients with clear complete or incomplete CSNB and excluded for mutations in known genes, we estimate that approximately 20% of them may carry mutations in a novel gene. This is a strong indication that mutations in other genes remain to be discovered or that mutations in regulatory elements and introns, might be involved. The expression, immunolocalization, function and pathogenic mechanisms of some of those genes are well understood. Although we know that NYX, TRPM1, GPR179 and LRIT3 transcripts and proteins are localized in bipolar cells, further studies need to be performed to better understand the role of these molecules and localize them correctly to the poorly understood photoreceptor-bipolar retinal signaling cascade. To decipher this in more detail in vivo or ex vivo using mouse models seems to be most appropriate. Since cCSNB mouse models show the same congenital, non progressive and stationary night blindness phenotype, this disease seems to be also the perfect model to develop a gene therapy approach. Indeed, recent studies using a transgenic approach and an AAV-approach in mice lacking NYX showed partly rescue of the protein localization and ERG-phenotype. Together our ongoing project for the last two years aimed to continue using state-of-the-art strategies to identify known and novel gene defects underlying stationary as well as progressive inherited retinal disorders, to functionally characterize genes underlying the complete form of CSNB and develop a gene therapy approach for the GRM6 and LRIT3 gene defect in mice. 

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