Prof. Dr. Wolfgang Berger

 

Main Goals, Keywords

Molecular basis of retinal degenerations in human and mouse, identification of novel mutations in patiens with familial and sporadic retinal dystrophies, generation of mouse models by transgenic and gene targeting approaches, morphological analysis of retinal sections in mice, gene expression profiling, studies on the regulation of gene expression and splicing

Group Members

1 professor, 3 senior research fellows, 4 PhD students, 2 technicians, 3 master students, 1 secretary

Previous and Current Research

We identified by positional cloning and candidate gene approaches seven genes (CABP4, CACNA2D4, GRM6, NDP, NYX, RP2 and RPGR) that are mutated in familial and sporadic forms of human eye diseases. For part of them, the precise role of the corresponding gene product(s) in retinal tissue is unknown.

Patients with Norrie disease (NDP, Norrie disease pseudoglioma) are blind from birth and deafness and/or mental retardation can occur later in life. Mutations in the NDP gene can also give rise to other eye diseases. We established a mouse model for the disease which resembles the human Norrie disease phenotype in eye and ear. Current work on this mouse line includes gene expression profiling and the identification of additional genetic factors which influence clinical variability.

Mutations in NYX cause a congenital form of night blindness (CSNB1). We are investigating the role of specific protein motifs through transient expression in different cell lines. Additionally, the transcriptional control of this gene is being studied by analysing putative promoter and enhancer elements in reporter gene assays.

RP2 and RPGR mutations cause the most frequent forms of X-chromosomal retinitis pigmentosa (RP2 and RP3). Knock-in and transgenic mouse lines have been established for RPGR which are currently being characterised.

Another project focuses on a defect in retinal ribbon synapses. The mutation is transmitted in an autosomal recessive manner and we mapped the locus in the mouse genome and identified the causative mutation in the Cacna2d4 gene, encoding a regulatory subunit of a retinal calcium channel. Very recently, mutation screening of CACNA2D4 in human patients revealed a disease associated DNA sequence variation in a family with a mild form of cone dystrophy.

Future Projects

Analysis of complex pathophysiological processes in different mouse models for human forms of retinal degenerations by genomics and proteomics, identification of disease modifying/modulating factors, influence of the genetic background on disease expression and clinical variability, elucidation of gene defects in patients with classic monogenic and oligogenic forms of retinal degenerations as well as multifactorial diseases including age-related macular degeneration

Techniques and Equipment

molecular biological techniques, histology, light microscopy, fluorescence microscopy, cell culture and transfection assays, luciferase reporter assays (Luminoskan), realtime RT-PCR (TaqMan), DNA sequencing (ABI Prism 3100), automated DNA fragment analysis (ABI Prism 310), immunocytochemistry.

Selected Publications

• Schäfer, N.F., Luhmann, U.F., Feil, S., Berger, W. Differential gene expression in Ndph knockout mice in retinal development. Invest Ophthalmol Vis Sci 50:906-916 (2009).
• Tanner, G., Glaus, E., Barthelmes, D., Ader, M., Fleischhauer, J., Pagani, F., Berger, W., Neidhardt, J. Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA. Hum Mutat 30:255-263 (2009).
  
• Kloeckener-Gruissem, B., Vandekerckhove, K., Nurnberg, G., Neidhardt, J., Zeitz, C., Nurnberg, P., Schipper, I., Berger, W. Mutation of the solute carrier SLC16A12 associates with a syndrome combining autosomal dominant juvenile cataract with microcornea and glucosuria. Am J Hum Genet 82:772-779 (2008).
  

Selected Lectures, Seminars or Colloquia

• Medical Genetics
• Classic Mendelian Genetics
• Human Molecular Genetics
• Retina Meeting (joint seminar of research groups Berger/
  Neuhauss/Remé; including guest lectures)

Funding

British Retinitis Pigmentosa Society (BRPS, UK), Deutsche Forschungsgemeinschaft (DFG), EMDO Foundation Zurich, Foundation Fighting Blindness (FFB, USA), Hartmann Müller-Foundation, Jackstätt Stiftung, Swiss National Science Foundation (SNF), Velux Foundation

URL

http://www.medmolgen.uzh.ch