A novel mutation in the FOXC1 gene in a family with Axenfeld-Rieger syndrome and Peters'anomaly

Molecular Genetics Laboratory, Institute for Ophthalmic Research, University Clinics Tuebingen, Tuebingen, Germany.
Clinical Genetics (Impact Factor: 3.93). 06/2008; 74(5):476-80. DOI: 10.1111/j.1399-0004.2008.01025.x
Source: PubMed


Peters anomaly and Axenfeld-Rieger syndrome (ARS) belong to the overlapping spectrum of disorders summarized as anterior segment dysgenesis (ASD). Five patients from a family with Peters' anomaly and ARS were screened for mutations in the PITX2, CYP1B1 and FOXC1 genes by direct sequencing. All affected family members examined were heterozygous for a single nucleotide substitution, resulting in a nonsense mutation (Q120X) at a highly conserved residue of the FOXC1 gene that is essential for DNA binding. In this pedigree, all affected family members were diagnosed with ARS except for one who shows bilateral Peters' anomaly. Our findings support the role of FOXC1 mutations in the spectrum of ASD.

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    • "Axenfeld-Rieger syndrome (ARS) is a complex autosomal dominant disorder primarily characterized by anomalies of the anterior segment of the eye, face, teeth, and umbilical stump. Congenital heart defects, including ASD, pseudotruncus arteriosus, and mitral valve and intraventricular septal defects have also been reported in a number of patients with ARS (Akkus and Argin, 2010; Antevil and others, 2009; Aysenur Pac and others, 2008; Baruch and Erickson, 2001; Bekir and Gungor, 2000; Calcagni and others, 2006; Cunningham and others, 1998; Davies and others, 1999; Grosso and others, 2002; Maclean and others, 2005; Mammi and others, 1998; Weisschuh and others, 2008). Linkage analyses have identified four different loci in humans, 4q25, 6p25, 13q14, and 16q24, each of which has been independently associated with ARS. "
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    • "FOXC1 whole gene deletions or mutations within or affecting the forkhead domain through which FOX proteins are able to interact with DNA and translocate to the cell nuclei [29] underlie Axenfeld-Rieger anomalies. To date, at least 30 different missense, nonsense, and frameshift mutations have been identified, affecting the forkhead domain of FOXC1 in individuals presenting with the spectrum of ocular defects associated with Axenfeld-Rieger syndrome and anomaly (anteriorly-displaced Schwalbe’s line, iris adhesions, iridocorneal angle dysgenesis, and corectopia [30-44]). Approximately half of these patients also develop glaucoma, which may cause further visual deterioration. "
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    ABSTRACT: Haploinsufficiency through mutation or deletion of the forkhead transcription factor, FOXC1, causes Axenfeld-Rieger anomaly, which manifests as a range of anterior segment eye defects and glaucoma. The aim of this study is to establish whether mutation of FOXC1 contributes toward other developmental eye anomalies, namely anophthalmia, microphthalmia, and coloboma. The coding sequence and 3;-UTR of FOXC1 was analyzed in 114 subjects with severe developmental eye anomalies by bidirectional direct sequencing. Four coding FOXC1 variations (two novel missense variations, one insertion, and one novel deletion) were identified in the cohort. Two noncoding variations were also identified in the 3'-UTR. The missense mutations were c.889C_T and c.1103C_A, resulting in p.Pro297Ser and p.Thr368Asn, respectively. The c.889C_T transition was identified in 19 of the 100 unaffected control samples. The c.1103C_A transversion resulted in a conservative substitution in an unconserved amino acid and was deemed unlikely to be pathogenic. A c.1142_1144insGCG change resulting in p.Gly380ins, which was previously associated with kidney anomalies, was identified in 44 of the 114 affected individuals. This variation was also present in 29 of the 87 unaffected controls and is therefore likely to be a polymorphism. A c.91_100delCGGCGGCCG deletion resulting in p.Ala31_33del was identified in one individual. This deletion segregated with the moderately affected mother and unaffected maternal grandfather of the proband. This deletion was identified in one of the 307 unaffected controls. Our data suggests a potential susceptibility role for FOXC1 in generating severe eye pathologies. However, on the basis of these results, it is unlikely that FOXC1 mutation is a major causative factor of anophthalmia, microphthalmia, and coloboma.
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