Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia.

Autor:	Chekuri A; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.; Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA, USA., Logan EM; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA., Krauson AJ; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA., Salani M; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA., Ackerman S; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA., Kirchner EG; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA., Bolduc JM; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA., Wang X; Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA, USA., Dietrich P; Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN, USA., Dragatsis I; Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN, USA., Vandenberghe LH; Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA, USA., Slaugenhaupt SA; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA., Morini E; Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2022 Jun 04; Vol. 31 (11), pp. 1776-1787.
DOI:	10.1093/hmg/ddab359
Abstrakt:	Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspects of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; IkbkapΔ20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477. (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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