Characterization of the retinal phenotype in a humanized FD mouse model with defective ELP1 splicing.

Abstract

Purpose : Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disorder caused by a splice mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in skipping of exon 20 and tissue specific reduction of ELP1 protein levels, predominantly in the central and peripheral nervous system. Although FD patients exhibit a complex neurological phenotype due to the degeneration of sensory and autonomic neurons, progressive retinal degeneration severely impacts quality of life. Two different mouse models have been previously generated to study the retinal phenotype that results from complete loss of ELP1. However, neither of these models accurately recapitulates the tissue specific defective splicing observed in FD patients. Therefore, we developed a novel FD phenotypic mouse model by introducing a transgene carrying the human ELP1 gene with the FD splice mutation (TgFD9) into a hypomorphic mouse that expresses low levels of endogenous Elp1 (Elp1^△20/flox). This mouse model displays both the clinical features of the disease and the tissue specific mis-splicing observed in FD patients.

Methods : Detailed characterization of the retinal phenotype in the FD mouse model was performed to investigate the pathology associated with the splice mutation in ELP1. Optical Coherence Tomography (OCT) was performed to investigate retinal thickness and retinal morphology was studied using H and E staining. Retinal ganglion cell (RGC) cell counting was performed using retinal whole mounts.

Results : Optical Coherence Tomography (OCT) analysis to investigate retinal thickness revealed significant reduction in the thickness of the retinal nerve fiber layer (RFNL) and Ganglion cell layer (GCL) when compared to control littermates. Analysis of retinal morphology revealed progressive loss of RGC's. Results from whole mount analysis also indicated the loss RGC's in the FD mouse model.

Conclusions : Our findings suggest that our novel FD mouse model recapitulates optic neuropathy observed in FD patients and will provide a platform to test the in vivo efficacy of ELP1 splicing modulation to increase functional ELP1 in the retina.

This is a 2020 ARVO Annual Meeting abstract.