Pitx3 directly regulates Foxe3 during early lens development

Ahmad, Nafees; Aslam, Muhammad; Muenster, Doris; Horsch, Marion; Khan, Muhammad Amir; Carlsson, Peter; Beckers, Johannes; Graw, Jochen

doi:10.1387/ijdb.130193jg

Cited by 29 publications

(35 citation statements)

References 58 publications

(53 reference statements)

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“…The spontaneous mutation aphakia (ak) is recessive and causes a small eye phenotype with the absence of lens and eyelids (Grimm et al, 1998;Varnum & Stevens, 1968). Pitx3 was mapped near the ak locus on mouse chromosome 19 and its expression was absent in ak/ak homozygous mutant lens (Semina et al, 1997(Semina et al, , 2000 (Ahmad et al, 2013). Interestingly, pitx3 knockdown in zebrafish results lens and retina defects and in reduced foxe3 lens expression (Shi et al, 2005(Shi et al, , 2006), suggesting that PITX3 mediated regulation of FOXE3 is conserved in vertebrates.…”

Section: Pitx3 Animal Models and Mechanistic Insights Into The Patholmentioning

confidence: 99%

Mutation update of transcription factor genesFOXE3,HSF4,MAF, andPITX3causing cataracts and other developmental ocular defects

et al. 2018

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Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.

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Section: Pitx3 Animal Models and Mechanistic Insights Into The Patholmentioning

confidence: 99%

Mutation update of transcription factor genesFOXE3,HSF4,MAF, andPITX3causing cataracts and other developmental ocular defects

et al. 2018

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“…TFAP2A has been shown to be responsive to retinoic acid, to inhibit the WNT pathway (Li and Dashwood 2004) and be involved in PITX2 regulation (Bamforth et al 2004). PAX6 deficiency has been shown to negatively affect FOXE3 (Blixt et al 2007) and PITX3 expression (Chauhan et al 2002); PITX3 has been reported to directly regulate FOXE3 expression (Shi et al 2006; Ahmad et al 2013). PAX6 and TFAP2A have been demonstrated to physically interact and promote transcription of some corneal genes (Sivak et al 2004).…”

Section: Figmentioning

confidence: 99%

Whole exome sequence analysis of Peters anomaly

et al. 2014

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Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the frst study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.

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“…This mutation lets the homeodomain intact, but more than the half of the C-terminal part (including the OAR region) is lost (Wada et al, 2014). In the developing lens, Foxe3 is a direct target gene of PITX3 (Ahmad et al, 2013).…”

Section: Eye and Parkinson's Disease: Pitx3mentioning

confidence: 99%

From eyeless to neurological diseases

Graw

2017

Experimental Eye Research

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Age-related cataracts are frequently associated with degenerative changes in the ocular lens including the aggregation of proteins - mainly crystallins, but also other proteins including amyloids (Aβ) leading to the hypothesis that cataracts could be used as "biomarkers" for Alzheimer disease. Even if this hypothesis was rejected by David Beebe's last paper (Bei et al., Exp. Eye Res., 2015), it is a fascinating aspect to look for commonalities between eye diseases and neurological disorders. In this review, I discuss such commonalities between eye and brain mainly from a developmental point of view. The finding of the functional homology of the Drosophila eyeless gene with the mammalian Pax6 gene marks a first highlight in the developmental genetics of the eye - this result destroyed the "dogma" of the different evolutionary routes of eye development in flies and mammals. The second highlight was the finding that Pax6 is also involved in the development of the forebrain supporting the pleiotropic role of many genes. These findings opened a new avenue for research showing that a broad variety of transcription factors, but also structural proteins are involved both, in eye and brain development as well as into the maintenance of the functional integrity of the corresponding tissue(s). In this review recent findings are summarized demonstrating that genes whose mutations have been identified first to be causative for congenital or juvenile eye disorders are also involved in regenerative processes and neurogenesis (Pax6), but also in neurodegenerative diseases like Parkinson (e.g. Pitx3) or in neurological disorders like Schizophrenia (e.g. Crybb1, Crybb2).

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Pitx3 directly regulates Foxe3 during early lens development

Cited by 29 publications

References 58 publications

Mutation update of transcription factor genesFOXE3,HSF4,MAF, andPITX3causing cataracts and other developmental ocular defects

Mutation update of transcription factor genesFOXE3,HSF4,MAF, andPITX3causing cataracts and other developmental ocular defects

Whole exome sequence analysis of Peters anomaly

From eyeless to neurological diseases

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