Autosomal dominant iris hypoplasia is caused by a mutation in the rieger syndrome (rieg/pitx2) gene

Alward, Wallace L.M.; Semina, Elena V.; Kalenak, Jeffrey W.; Hèon, Elise; Sheth, Bhavna P.; Stone, Edwin M.; Murray, Jeffrey C.

doi:10.1016/s0002-9394(99)80242-6

Cited by 127 publications

(62 citation statements)

References 5 publications

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“…PITX2 mutations have also been associated with Peters anomaly, 41 iris hypoplasia/iridogoniodysgenesis syndrome, 42,43 and ring dermoid of the cornea, 44 but these are single cases and PITX2 mutations are mainly detected in ARS patients with systemic changes.…”

Section: Pitx2 Defects and Arsmentioning

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 Defects and Arsmentioning

confidence: 99%

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

2009

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“…The gene PITX2 ("pituitary homeobox transcription factor 2", RIEG1) was cloned on chromosome 4p25 and regulates the expression of other genes during embryonic development 11 . Several pathological mutations (deletions, translocations or spot mutations) in PITX2 have been described causing different phenotypes, including AR malformation 11 , iridogoniodysgenesis 12 , iris hypoplasia 13 and rarely Peters' anomaly 14 . A second gene associated with AR syndrome is FOXC1 ("Forkhead Box C1"), on chromosome 6p25 15 .…”

Section: Discussionmentioning

confidence: 99%

“…These mutations produce a very large spectrum of phenotypes of anterior segment dysgenesis, mild to severe form, including or not systemic manifestations. [15][16][17] Other locus for Rieger syndrome was mapped on 13q14 (RIEG2) 13 , but no gene was identified 18 . Besides the genes described previously, there are evidences of the involvement of PAX6 gene ("Paired Box Gene 6") in 11p13 chromosome and MAF gene ("V-MAF Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog") in 16q24 chromosome on AR malformations 4 .…”

Section: Discussionmentioning

confidence: 99%

Axenfeld-Rieger anomaly and corneal endothelial dystrophy: a case series

Oliveira¹,

Mitraud²,

Yamane³

2008

Rev. bras.oftalmol.

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Report of a study of a family with a remarkable combination of endothelial corneal dystrophy, and anterior chamber dysgenesis classified as Axenfeld-Rieger anomaly. A 56 year-old female had blurred vision complaints. A slit lamp evaluation showed a bilateral posterior embryotoxon and guttata with corneal edema, Descemet membrane's folds, characterizing Fuchs endothelial dystrophy. A 27 year-old daughter was asymptomatic. The biomicroscopic exam disclosed a bilateral nasal and temporal posterior embryotoxon and a central guttata. Gonioscopy showed iridocorneal strands with a prominent Schwalbe´s line. The intraocular pressure was normal. Her sister, a 25 year-old female presented very similar abnormalities along with her brother (22 years old). A 19 year-old female sister presented the iridocorneal angle alterations, without Fuchs endothelial dystrophy, until this moment. This paper presents a family with a central cornea guttata or Fuchs dystrophy associated with Axenfeld-Rieger anomaly. Two different inherited diseases appearing together in an entire family may suggest a single molecular and genetic etiology, with high penetrance.

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“…Numerous pathologic PITX2 mutations including missense variations, splice site alterations, and insertions/deletions have been described, producing a continuum of clinical phenotypes including Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis, and iris hypoplasia (5,9,10), as well as rarer cases of a Peters-like anomaly (11). Of these, ϳ82% of PITX2 mutations were observed in ARS, ϳ7% were observed both in iridogoniodysgenesis and in iris hypoplasia, and less than 3% were observed in Peters-like anomaly (Human Gene Mutation Database (HGMD)).…”

Section: Pituitary Homeobox Transcription Factor 2 (Pitx2)mentioning

confidence: 99%

Human PRKC Apoptosis WT1 Regulator Is a Novel PITX2-interacting Protein That Regulates PITX2 Transcriptional Activity in Ocular Cells

Acharya

Lingenfelter

Huang

et al. 2009

Journal of Biological Chemistry

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Mutations in the homeobox transcription factor PITX2 result in Axenfeld-Rieger syndrome (ARS), which is associated with anterior segment dysgenesis and an increased risk of glaucoma. To understand the pathogenesis of the defects resulting from PITX2 mutations, it is essential to know the normal functions of PITX2 and its interaction with the network of proteins in the eye. Yeast two-hybrid screening was performed using a cDNA library from a human trabecular meshwork primary cell line to detect novel PITX2-interacting proteins and study their role in ARS pathogenesis. After screening of ϳ1 ؋ 10 6 clones, one putative interacting protein was identified named PRKC apoptosis WT1 regulator (PAWR). This interaction was further confirmed by retransformation assay in yeast cells as well as co-immunoprecipitation in ocular cells and nickel pulldown assay in vitro. PAWR is reportedly a proapoptotic protein capable of selectively inducing apoptosis primarily in cancer cells. Our analysis indicates that the homeodomain and the adjacent inhibitory domain in PITX2 interact with the C-terminal leucine zipper domain of PAWR. Endogenous PAWR and PITX2 were found to be located in the nucleus of ocular cells and to co-localize in the mesenchyme of the iridocorneal angle of the developing mouse eye, consistent with a role in the development of the anterior segment of the eye. PAWR was also found to inhibit PITX2 transcriptional activity in ocular cells. These data suggest PAWR is a novel PITX2-interacting protein that regulates PITX2 activity in ocular cells. This information sheds new light in understanding ARS and associated glaucoma pathogenesis. Pituitary homeobox transcription factor 2 (PITX2)2 is a member of the paired-bicoid family of homeodomain (HD) transcription factors. Members of pituitary homeobox proteins are actively involved in a wide range of developmental processes including formation of pituitary gland and hind limb and of anterior segment of the eye as well as brain morphogenesis (1-3). Expression of PITX2 is found during ocular development (4, 5). The PITX2 gene is represented by several different splicing and transcriptional isoforms. The four best characterized are PITX2A, -B, -C (5), and -D (6) These isoforms of PITX2 vary in their N termini but share common HD and C-terminal sequences. The PITX2D isoform, however, has a truncated and non-functional HD (7). These alternate transcripts (A, B, and C) encode 271, 317, and 324 amino acids, respectively (4, 8).Numerous pathologic PITX2 mutations including missense variations, splice site alterations, and insertions/deletions have been described, producing a continuum of clinical phenotypes including Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis, and iris hypoplasia (5, 9, 10), as well as rarer cases of a Peters-like anomaly (11). Of these, ϳ82% of PITX2 mutations were observed in ARS, ϳ7% were observed both in iridogoniodysgenesis and in iris hypoplasia, and less than 3% were observed in Peters-like anomaly (Human Gene Mutation Database (HGMD)). ARS itself...

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Autosomal dominant iris hypoplasia is caused by a mutation in the rieger syndrome (rieg/pitx2) gene

Cited by 127 publications

References 5 publications

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Axenfeld-Rieger anomaly and corneal endothelial dystrophy: a case series

Human PRKC Apoptosis WT1 Regulator Is a Novel PITX2-interacting Protein That Regulates PITX2 Transcriptional Activity in Ocular Cells

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