Rieger syndrome: a clinical, molecular, and biochemical analysis

Amendt, Brad A.; Semina, Elena V.; Alward, Wallace L.M.

doi:10.1007/pl00000647

Cited by 110 publications

(113 citation statements)

References 86 publications

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“…They all have identical C termini with a conserved 14-amino-acid OAR domain (otp, aristaless and rax), which is predicted to mediate protein -protein interactions and self-inhibitory interactions with the N terminus. 17 The smallest isoform, PITX2A (32 kDa), is the best studied with regards to ARS malformations and the PITX2 mutations reviewed in this study are described with regards to this isoform (Supplementary Figure 1). 18 The FOXC1 gene is a member of the forkhead family of transcription factors that play important roles in embryogenesis, tissue-specific gene expression and tumor development.…”

Section: Pitx2 and Foxc1mentioning

confidence: 99%

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

2009

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In association withAxenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations Axenfeld -Rieger syndrome (ARS) is a rare autosomal dominant disorder, which encompasses a range of congential malformations affecting the anterior segment of the eye. ARS shows genetic heterogeneity and mutations of the two genes, PITX2 and FOXC1, are known to be associated with the pathogenesis. There are several excellent reviews dealing with the complexity of the phenotype and genotype of ARS. In this study, we will attempt to give a brief review of the clinical features and the relevant diagnostic approaches, together with a detailed review of published PITX2 and FOXC1 mutations.

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Section: Pitx2 and Foxc1mentioning

confidence: 99%

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

2009

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“…Mutations in PITX2 were first identified as the molecular cause of the Rieger syndrome congenital malformations (Semina et al, 1996;Alward, 2000;Amendt et al, 2000). Pitx2 is expressed in many tissues during development, including the left lateral plate mesoderm, derivatives of the first brachial arch, the eye, brain, pituitary gland, mandible, heart, and limbs (Muccielli et al, 1996;Gage and Camper, 1997;Kitamura et al, 1997;Arakawa et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Pitx2c overexpression promotes cell proliferation and arrests differentiation in myoblasts

Martínez-Fernández

Hernández-Torres

Franco

et al. 2006

Developmental Dynamics

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Pitx2 is a paired-related homeobox gene that has been shown to play a central role during development. In the mouse, there are three isoforms, Pitx2a, b, and c, which differ only in their amino terminal regions. Pitx2 is expressed in myotomes, myoblasts, and myofibers and may be involved in muscle patterning. However, the mechanism by which Pitx2 acts in muscle cell lineages as well as the distinct functions of the individual isoforms have not been investigated. In this study, we used Sol8 myoblasts to investigate the function of Pitx2 in skeletal myogenesis. We found that Pitx2c is the main Pitx2 isoform present in Sol8 myoblasts. Overexpression of Pitx2c in Sol8 myoblasts inhibited myocyte differentiation and myotube formation. Furthermore, Sol8 cells overexpressing Pitx2c maintained high proliferative capacity and a significant up-regulation of the cell cycle genes cyclin D1, cyclin D2, and c-myc. Gene expression analysis for Pax3 and the s MyoD and myogenin showed that Pitx2c-overexpression caused Sol8 cells to remain as myoblasts, in an undifferentiated myogenic state. Furthermore, down-regulation of the muscle-specific genes sTnI and MyHC3 demonstrated that Sol8-overexpressing Pitx2c myoblasts failed to reach terminal differentiation. This study sheds light on previously unknown functions of the Pitx2c isoform in balancing proliferation vs. differentiation in a myogenic cell line.

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“…PITX2 mutations are causative for Axenfeld-Rieger syndrome, which was defined as a genetic disorder in 1935 (7). It is an autosomal dominant human disorder characterized by dental hypoplasia, mild craniofacial dysmorphism, ocular anterior chamber anomalies causing glaucoma, and umbilical stump abnormalities (4,8). Abnormal cardiac development associated with AxenfeldRieger syndrome can affect outflow tract structures.…”

mentioning

confidence: 99%

PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

Ganga

Espinoza

Cox

et al. 2003

Journal of Biological Chemistry

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PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2؊/؊ mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor (ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.

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Rieger syndrome: a clinical, molecular, and biochemical analysis

Cited by 110 publications

References 86 publications

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Pitx2c overexpression promotes cell proliferation and arrests differentiation in myoblasts

PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

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