Mutations of the Forkhead/Winged-Helix Gene, FKHL7, in Patients with Axenfeld-Rieger Anomaly

Mears, Alan J.; Jordan, Tim; Mirzayans, Farideh; Dubois, Stéphane; Kume, Tsutomu; Parlee, Michael; Ritch, Robert; Koop, Ben F.; Kuo, Wen Lin; Collins, Colin C.; Marshall, Jody; Gould, Douglas B.; Pearce, W G; Carlsson, Peter; Enerbäck, Sven; Morissette, Jean; Bhattacharya, Siladitya; Hogan, Brigid L.M.; Raymond, Vincent; Walter, Michael A.

doi:10.1086/302109

Cited by 291 publications

(235 citation statements)

References 43 publications

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“…ARS has been associated with mutations of two known genes: PITX2 (the pituitary homeobox 2 gene) at 4q25 9 and, FOXC1 (the forkhead box C1 gene, FKHL7) at 6p25. 10,11 A third locus was suggested by deletion of 13q14, supported by linkage analyses, but a disease-causing gene has not been identified yet. 12,13 In two isolated cases, deletion of the 16q23-q24 region 14 and deletion of the PAX6 gene at 11p13, 15 respectively, were related to ARS, but these findings were not supported by other studies.…”

Section: Genetic Basis Of 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: Genetic Basis Of Arsmentioning

confidence: 99%

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

2009

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“…Deleterious sequence variants in the FOXC1 (6p25.3, MIM 601090) 6,7 and PITX2 genes (4q25, MIM 601542), 8 as well as two additional loci (RIEG2 at 13q14 and 16q24), 9,10 have been associated with ARS. In addition, several copy number variants and chromosomal rearrangements disrupting FOXC1 or PITX2 have been reported in association with ARS.…”

Section: Introductionmentioning

confidence: 99%

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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“…4 However, mutations in the PITX2 gene are not the sole cause of ASD; at least four other gene loci have been identified on 6p25, 13q14 and 16q24, and 11p13. [5][6][7] The genes FOXC1 and PAX6 at 6p25, and 11p13 respectively have been identified, 8,9 but the others remain elusive. Nonetheless, these and other studies have firmly established the fact that is ASD genetically heterogeneous (Table 1); more than one gene causes the 10 but now known to underlie a range of other ocular conditions 11 including Peters anomaly and a rare case of ARS.…”

Section: Classification Of Asdmentioning

confidence: 99%

Molecular and developmental mechanisms of anterior segment dysgenesis

Sowden

2007

Eye

136

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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Mutations of the Forkhead/Winged-Helix Gene, FKHL7, in Patients with Axenfeld-Rieger Anomaly

Cited by 291 publications

References 43 publications

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

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

Molecular and developmental mechanisms of anterior segment dysgenesis

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