Abstract
P 087
Retinal phenotype of a murine model of variant late-onset infantile lipofuscinosis (vLINCL)
Michael Dutescu1, Udo Bartsch2, Christos Skevas3, Sergej Skosyrski1, Cordula Dahlmann1, David A. Pearce4, Klaus Rüther1
1Augenklinik, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, 2Transplantationslabor, Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Hamburg-Eppendorf, Hamburg, 3Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Hamburg-Eppendorf, Hamburg, 4Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, USA
Objective
Mutations in the NCL6 gene have been linked to variant late-onset infantile lipofuscinosis (vLINCL), a disease causing progressive neurodegeneration, seizure and vision loss in affected individuals. So far, little is known about the function of the NCL6-encoded transmembrane protein and the underlying visual impairment in vLINCL. Only a few ocular phenotypes have been investigated in affected individuals showing the need for suitable disease models. To check whether a mouse model resembles the human condition, we performed ocular phenotype analysis on CLN6 mutant mice (nclf mice).
Methods
The Nclf mouse model, which harbours the c.316dupC CLN6 mutation, was raised against a C57BL/6 background mice and compared to corresponding controls. Electroretinogram (ERG) and pupillary light reflex analysis were performed at age 4, 9 and 12 month to estimate retinal function and vision. Enucleated eyes were subjected to histology and fluorescence microscopy.
Results
Nclf mice show accumulation of autofluorescent material in retinal cell layers. Reduction of scotopic ERG a- and b-wave potentials was observed at an age of 4 months. Cone responses, however, were normal at that time. At 9 months, there was no scotopic a-wave recordable, b-waves severely and cone responses moderately reduced. Finally, at 12 months the was no recordable ERG any more. Pupillary light reflex analysis revealed a progressive impairment of visual afference. Fluorescence angiograms were preformed to exclude vascular changes. Modest microangiopathic changes were observed in older animals compared to wild-type controls.
Conclusions
CLN6 mutant mice (Nclf mice) reveal a relatively slow retinal degeneration which can be classified as rod-cone-degeneration. At an age of 12 months there is no detectable retinal function any more. These mice can be used as a model to investigate the role of CLN6 in retinal structure and function and might serve to test therapeutic strategies.
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