Characterization and Prevalence of<i>PITX2</i>Microdeletions and Mutations in Axenfeld-Rieger Malformations

Lines, Matthew A.; Kozlowski, Kathy; Kulak, Stephen C.; Allingham, R Rand; Hèon, Elise; Ritch, Robert; Levin, Alex V.; Shields, M. Bruce; Damji, Karim F.; Newlin, Anna; Walter, Michael A.

doi:10.1167/iovs.03-0309

Cited by 64 publications

(61 citation statements)

References 40 publications

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“…5 Broad phenotypic variability associated with FOXC1 and PITX2 variants has been reported before, 11,14,17,18 as it has in this study, although Shields 5 previously reported that the severity of ocular defects did not correlate with the development of glaucoma. FOXC1 and PITX2 both encode developmental transcription factors expressed in a tightly regulated temporal and spatial manner during development.…”

Section: Discussionsupporting

confidence: 55%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

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Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P = 0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0 ± 13.0 years) compared with PITX2 carriers (18.0 ± 10.6 years, P = 0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P = 0.03) but became comparable at 25 years old (71.4% vs 57.7%, P = 0.38). These findings have important implications for the genetic counselling of families affected by AxenfeldRieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

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Section: Discussionsupporting

confidence: 55%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

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“…This finding provides further support for a potential role of PITX2 in SHORT syndrome and similar conditions. 18,29 Of particular note are three PITX2 mutations reported in our study. First, the deletion we identified involving the distant upstream region (but not the coding region) of PITX2 in one ARS patient is similar to our previously reported ARS case, 19 and thus our report highlights the importance of this recently discovered mechanism, loss of the upstream regulatory region, as a cause of ARS.…”

Section: Foxc1 Mutations: Phenotypes and Genotypesmentioning

confidence: 55%

“…The color reproduction of this figure is available at the European Journal of Human Genetics online. PITX2 and FOXC1 mutations in ocular syndromes LM Reis et al PITX2: 4.7% 18 and 16% 10 of ASD (neither study provided the proportion of ARS specifically). The variation is most likely due to differences in sample composition as our cohort is enriched with ARS cases with additional systemic defects, particularly dental and umbilical anomalies that appear to be strongly associated with PITX2 mutations.…”

Section: Foxc1 Mutations: Phenotypes and Genotypesmentioning

confidence: 95%

“…[15][16][17] Other types of PITX2 mutations include deletions of coding exons and chromosomal translocations. 5,6,18 A novel mechanism, deletion of an upstream regulatory region of PITX2, was recently reported in one patient with ARS. 19 Human FOXC1 mutations associated with ARS include missense mutations in the forkhead domain, nonsense and frameshift mutations throughout the gene, and whole gene deletions.…”

Section: Introductionmentioning

confidence: 96%

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PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Reis¹,

Tyler²,

et al. 2012

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Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.

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“…Chromosomal deletions including the PITX2 and FOXC1 genes leading to haploinsufficiency have been documented as causes of ARS. 29,30 In addition, several studies have demonstrated that duplication of FOXC1 can equally cause an ARS phenotype. 31,32 Overexpression of Pitx2 in animal models also causes ARS type phenotypes.…”

Section: Expression Of Asd Genesmentioning

confidence: 99%

Molecular and developmental mechanisms of anterior segment dysgenesis

Sowden

2007

Eye

138

102

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Anterior segment dysgenesis (ASD) is a failure of the normal development of the tissues of the anterior segment of the eye. It leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. Several different gene mutations have been identified underlying these anomalies with the majority of ASD genes encoding transcriptional regulators. In this review, the role of the ASD genes, PITX2 and FOXC1, is considered in relation to the embryology of the anterior segment, the biochemical function of these proteins, and their role in development and disease aetiology. The emerging view is that these genes act in concert to specify a population of mesenchymal progenitor cells, mainly of neural crest origin, as they migrate anteriorly around the embryonic optic cup. These same genes then regulate mesenchymal cell differentiation to give rise to distinct anterior segment tissues. Development appears critically sensitive to gene dosage, and variation in the normal level of transcription factor activity causes a range of anterior segment anomalies. Interplay between PITX2 and FOXC1 in the development of different anterior segment tissues may partly explain the phenotypic variability and the genetic heterogeneity characteristic of ASD.

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Characterization and Prevalence ofPITX2Microdeletions and Mutations in Axenfeld-Rieger Malformations

Abstract: Point mutations and gross deletions of PITX2 appear to produce an equivalent haploinsufficiency phenotype. Quantitative PCR is an efficient means of detecting causative PITX2 deletions in patients with AR and may increase the detection rate at this locus.

Cited by 64 publications

References 40 publications

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Molecular and developmental mechanisms of anterior segment dysgenesis

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