PITX2 Is Involved in Stress Response in Cultured Human Trabecular Meshwork Cells through Regulation of SLC13A3

Strungaru, M. Hermina; Footz, Tim; Liu, Yi; Berry, Fred B.; Belleau, Pascal; Semina, Elena V.; Raymond, Vincent; Walter, Michael A.

doi:10.1167/iovs.10-6967

Cited by 32 publications

(20 citation statements)

References 51 publications

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“…While proteins with which PITX2 and FOXC1 interact have been identified [33][34][35][36] and cellular pathways [37][38][39][40][41][42] have been implicated, the mechanisms underlying ASD are largely unknown. Thus, it remains unknown if COL4A1 mutations interact with Pitx2 and Foxc1 or if they represent a mechanistically distinct form of ASD.…”

Section: Discussionmentioning

confidence: 99%

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Mao¹,

Smith

Alavi³

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Mao M, Smith RS, Alavi MV, et al. Strain-dependent anterior segment dysgenesis and progression to glaucoma in Col4a1 mutant mice. Invest Ophthalmol Vis Sci. 2015;56:6823-6831. DOI:10.1167/iovs.15-17527 PURPOSE. Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma.METHODS. Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves.RESULTS. We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.CONCLUSIONS. Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.

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Section: Discussionmentioning

confidence: 99%

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Mao¹,

Smith

Alavi³

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…The recombinant expression plasmid, PITX2c-pcDNA4, which was constructed by Strungaru et al (54), was a gift from Professor Georges Christé, Physiopathologie des Troubles du Rythme Cardiaque, Faculté de Pharmacie de Lyon, Université Lyon 1, Lyon, France. The atrial natriuretic factor (ANF)-luciferase reporter plasmid, which contains the 2600-bp 5'-flanking region of the ANF gene, namely ANF(-2600)-Luc, was kindly provided by Dr Ichiro Shiojima, from the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.…”

Section: Methodsmentioning

confidence: 99%

A novel PITX2c loss-of-function mutation underlies lone atrial fibrillation

ZHOU

Zheng

Yang

et al. 2013

International Journal of Molecular Medicine

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Abstract. Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia responsible for substantial morbidity and significantly increased mortality rates. A growing body of evidence documents the important role of genetic defects in the pathogenesis of AF. However, AF is a heterogeneous disease and the genetic determinants for AF in an overwhelming majority of patients remain unknown. In the present study, a cohort of 100 unrelated patients with lone AF and a total of 200 unrelated, ethnically matched healthy individuals used as controls, were recruited. The whole coding exons and splice junctions of the pituitary homeobox 2c (PITX2c) gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in the 100 patients and 200 control subjects. The causative potential of the identified mutation of PITX2c was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutation were assayed using a dual-luciferase reporter assay system. Based on the results, a novel heterozygous PITX2c mutation (p.T97A) was identified in a patient with AF. The missense mutation was absent in the 400 reference chromosomes and was automatically predicted to be disease-causing. Multiple alignments of PITX2c protein sequences across species revealed that the altered amino acid was completely conserved evolutionarily. Functional analysis demonstrated that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings of the present study firstly link the PITX2c loss-of-function mutation to lone AF, and provide novel insight into the molecular mechanisms underlying AF, suggesting the potential implications for the early prophylaxis and allele-specific therapy of this common type of arrhythmia.

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“…The recombinant expression plasmid PITX2c-pcDNA4, which was constructed by Strungaru et al (55), was a gift from Professor Georges Christé, from Physiopathologie des troubles du rythme cardiaque, Faculté de Pharmacie de Lyon, Université Lyon 1, Lyon, France. The atrial natriuretic factor (ANF)-luciferase reporter plasmid, which contains the 2600-bp 5'-flanking region of the ANF gene, namely ANF(-2600)-Luc, was kindly provided by Dr Ichiro Shiojima, from the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine (Chiba, Japan).…”

Section: Alignment Of Multiple Pitx2c Protein Sequences Among Speciesmentioning

confidence: 99%

Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

Wei

Gong

Qiu

et al. 2014

International Journal of Molecular Medicine

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Abstract. Congenital heart disease (CHD) is the most common form of birth defect in humans and is the leading non-infectious cause of infant mortality. Emerging evidence strongly suggests that genetic risk factors play an important role in the pathogenesis of CHD. However, CHD is of pronounced genetic heterogeneity, and the genetic defects responsible for CHD in an overwhelming majority of patients remain unclear. In this study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeodomain transcription factor crucial for proper cardiovascular morphogenesis, was sequenced in 170 unrelated neonates with CHD. The available relatives of the mutation carriers and 200 unrelated ethnically matched healthy individuals were genotyped. The disease-causing potential of the PITX2c sequence variations was predicted by MutationTaster and PolyPhen-2. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, 2 novel heterozygous PITX2c mutations, p.R91Q and p.T129S, were identified in 2 unrelated newborns with transposition of the great arteries and ventricular septal defect, respectively. A genetic scan of the pedigrees revealed that each mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The mutations, which altered the amino acids completely conserved evolutionarily, were absent in 400 normal chromosomes and were predicted to be causative.Functional analysis revealed that the PITX2c mutations were both associated with significantly diminished transcriptional activity compared with their wild-type counterpart. This study demonstrates the association between PITX2c loss-of-function mutations and the transposition of the great arteries and ventricular septal defect in humans, providing further insight into the molecular mechanisms responsible for CHD.

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PITX2 Is Involved in Stress Response in Cultured Human Trabecular Meshwork Cells through Regulation of SLC13A3

Abstract: The results indicate that SLC13A3 is a direct downstream target of PITX2 transcriptional regulation and that levels of PITX2 and SLC13A3 modulate responses to oxidative stress in ocular cells.

Cited by 32 publications

References 51 publications

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

A novel PITX2c loss-of-function mutation underlies lone atrial fibrillation

Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

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