Cell death & disease, 2021-10, Vol.12 (11), p.1017-1017, Article 1017
2021
Details
- Autor(en) / Beteiligte
- Titel
- A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
- Ist Teil von
- Cell death & disease, 2021-10, Vol.12 (11), p.1017-1017, Article 1017
- Ort / Verlag
- England: Springer Nature B.V
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotypes and for developing therapeutic strategies. Here, we report the discovery of a new mouse model of early-onset glaucoma that bears a transversion substitution c. G344T, which results in a missense mutation, p. R115L in PITX2. The mutation causes an elevation in intraocular pressure (IOP) and progressive death of retinal ganglion cells (RGC). These ocular phenotypes recapitulate features of pathologies observed in human glaucoma. Increased oxidative stress was evident in the inner retina. We demonstrate that the mutant PITX2 protein was not capable of binding to Nuclear factor-like 2 (NRF2), which regulates Pitx2 expression and nuclear localization, and to YAP1, which is necessary for co-initiation of transcription of downstream targets. PITX2-mediated transcription of several antioxidant genes were also impaired. Treatment with N-Acetyl-L-cysteine exerted a profound neuroprotective effect on glaucoma-associated neuropathies, presumably through inhibition of oxidative stress. Our study demonstrates that a disruption of PITX2 leads to glaucoma optic pathogenesis and provides a novel early-onset glaucoma model that will enable elucidation of mechanisms underlying the disease as well as to serve as a resource to test new therapeutic strategies.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-4889eISSN: 2041-4889DOI: 10.1038/s41419-021-04331-1Titel-ID: cdi_doaj_primary_oai_doaj_org_article_9b0f4f8944f54dbcbeb552e3224422c3
- Format
- –
- Schlagworte
- Acetylcysteine, Age, Animal models, Animals, Antioxidants, Apoptosis - genetics, Blindness, Cell death, Disease Models, Animal, Female, Glaucoma, Glaucoma - genetics, Glaucoma - metabolism, HEK293 Cells, Homeobox Protein PITX2, Homeodomain Proteins - genetics, Homeodomain Proteins - metabolism, Humans, Intraocular Pressure, Localization, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Missense mutation, Mutation, Mutation, Missense, Neuroprotection, NF-E2-Related Factor 2 - metabolism, Optic neuropathy, Oxidative stress, Phenotype, Phenotypes, Pitx2 protein, Retina, Retinal ganglion cells, Retinal Ganglion Cells - metabolism, Signal Transduction - genetics, Transcription Factors - genetics, Transcription Factors - metabolism, Transcription initiation, Transfection, Transversion, YAP-Signaling Proteins - metabolism, Yes-associated protein