Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
04 06 2022
04 06 2022
Historique:
received:
08
06
2021
revised:
09
12
2021
accepted:
10
12
2021
pubmed:
16
12
2021
medline:
9
6
2022
entrez:
15
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34908112
pii: 6462338
doi: 10.1093/hmg/ddab359
pmc: PMC9169455
doi:
Substances chimiques
Ikbkap protein, mouse
0
Intracellular Signaling Peptides and Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1776-1787Subventions
Organisme : NEI NIH HHS
ID : R01 EY029544
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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