The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25

Abstract

A number of different eye disorders with the presence of early-onset glaucoma as a component of the phenotype have been mapped to human chromosome 6p25. These disorders have been postulated to be either allelic to each other or associated with a cluster of tightly linked genes. We have identified two primary congenital glaucoma (PCG) patients with chromosomal anomalies involving 6p25. In order to identify a gene involved in PCG, the chromosomal breakpoints in a patient with a balanced translocation between 6p25 and 13q22 were cloned. Cloning of the 6p25 breakpoint led to the identification of two candidate genes based on proximity to the breakpoint. One of these, FKHL7, encoding a forkhead transcription factor, is in close proximity to the breakpoint in the balanced translocation patient and is deleted in a second PCG patient with partial 6p monosomy. Furthermore, FKHL7 was found to harbour mutations in patients diagnosed with Rieger anomaly (RA), Axenfeld anomaly (AA) and iris hypoplasia (IH). This study demonstrates that mutations in FKHL7 cause a spectrum of glaucoma phenotypes.

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

“…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.…”

“…45,46 Balanced chromosome rearrangements involving FOXC1 or its surrounding landscape are rare, but a balanced t(6;13) translocation in an ARS patient lead to identification of FOXC1, as a causative gene for this disorder. 11 On the other hand, there are more than 40 deletions, either interstitial or telomeric, involving 6p25 45,47,48 and the patients frequently present with ocular, craniofacial, skeletal, cardiac, and renal malformations, hearing loss, and hydrocephalus. 47 The phenotypic variation seen in these patients are largely because of the size of the deletions and the genes involved.…”

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

“…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.…”

Molecular and developmental mechanisms of anterior segment dysgenesis

“…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.…”

“…7,12,13 As well as causing ARS, PITX2, and FOXC1 mutations have been demonstrated in cases of Peters anomaly and primary congenital glaucoma (PCG). 9,14,15 Peters anomaly has also been associated with mutations in two other genes, the CYP1B1 gene, commonly mutated in PCG and the FOXC1 related gene, FOXE3. 16 These findings indicate that PCG may also be considered as part of the ASD spectrum affecting common and interacting genetic pathways.…”