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. 2010 Jun 23;16:1162-8.

Homozygous FOXE3 Mutations Cause Non-Syndromic, Bilateral, Total Sclerocornea, Aphakia, Microphthalmia and Optic Disc Coloboma

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Homozygous FOXE3 Mutations Cause Non-Syndromic, Bilateral, Total Sclerocornea, Aphakia, Microphthalmia and Optic Disc Coloboma

Manir Ali et al. Mol Vis. .
Free PMC article

Abstract

Purpose: To investigate the genetic basis of recessively-inherited congenital, non syndromic, bilateral, total sclerocornea in two consanguineous pedigrees, one from the Punjab province of Pakistan and the other from the Tlaxcala province of Mexico.

Methods: Ophthalmic examinations were conducted on each family member to confirm their diagnosis and magnetic resonance imaging (MRI) or ultrasonography of the eyes was performed on some family members. Genomic DNA was analyzed by homozygosity mapping using the Affymetrix 6.0 SNP array and linkage was confirmed with polymorphic microsatellite markers. Candidate genes were sequenced.

Results: A diagnosis of autosomal recessive sclerocornea was established for 7 members of the Pakistani and 8 members of the Mexican pedigrees. In the Pakistani family we established linkage to a region on chromosome 1p that contained Forkhead Box E3 (FOXE3), a strong candidate gene since FOXE3 mutations had previously been associated with various anterior segment abnormalities. Sequencing FOXE3 identified the previously reported nonsense mutation, c.720C>A, p.C240X, in the Pakistani pedigree and a novel missense mutation which disrupts an evolutionarily conserved residue in the forkhead domain, c.292T>C, p.Y98H, in the Mexican pedigree. Individuals with heterozygous mutations had no ocular abnormalities. MRI or ultrasonography confirmed that the patients with sclerocornea were also aphakic, had microphthalmia and some had optic disc coloboma.

Conclusions: This is the fourth report detailing homozygous FOXE3 mutations causing anterior segment abnormalities in human patients. Previous papers have emphasized aphakia and microphthalmia as the primary phenotype, but we find that the initial diagnosis - and perhaps the only one possible in a rural setting - is one of non-syndromic, bilateral, total sclerocornea. Dominantly inherited anterior segment defects have also been noted in association with heterozygous FOXE3 mutations. However the absence of any abnormalities in the FOXE3 heterozygotes described suggests that genetic background and environmental factors plays a role in the penetrance of the mutant allele.

Figures

Figure 1
Figure 1
Clinical description of the families. A: The pedigree structures are shown for MEP54 and the Mexican pedigree. Affected individuals are depicted with filled-in symbols. The numbers highlight the family members from whom blood was taken for DNA extraction. B: Anterior segment photos were taken using a Nixon Camera for affected member 1971 (aged 8 years) from the Pakistani and 1855 (aged 12 years), 1652 (aged 40 years), 1655 (aged 38 years) and 1851 (aged 48 years) from the Mexican pedigrees. Note total sclerocornea. Acuity was hand movements only.
Figure 2
Figure 2
Molecular analysis of the Pakistani pedigree. A: Confirmatory microsatellite genotyping highlighted a homozygous region on chromosome 1q between the markers D1S496 and D1S200 as being linked with the disease phenotype. The physical distance for each marker is represented based on the human February 2009 assembly (hg19) of the UCSC Genome Browser. The FOXE3 gene is marked within the refined interval at 47.9Mb. B: The sequencing chromatogram shows the c.720C>A mutation in the FOXE3 gene in an affected member of the Pakistani pedigree.
Figure 3
Figure 3
Molecular analysis of the Mexican pedigree. A: Sequencing chromatogram showing the c.292T>C mutation in the FOXE3 gene in an affected member of the Mexican pedigree. B: Protein sequence conservation. Diagram showing part of the amino acid sequence of the FOXE3 protein within the forkhead domain. Note the evolutionary conserved tyrosine (Y) residue in the normal sequence that is mutated to a histidine in the patients with sclerocornea. The F93 and F98 residues that are mutated to give rise to the dysgenetic lens mouse mutant are also depicted. C: Structural model of the forkhead domain of human FOXE3 wildtype and p.Y98H. (i) Ribbon representation of the DNA – fork head domain complex. DNA is depicted in gray and forkhead domain in red, yellow or green depending if helix, beta strand or loop regions. Structural microenvironment of Y98 (ii) and H98 (iii), residues within 6 Angstrom of Y98, or H98, is shown in stick representation and labeled in black boxes. (iv) Structural overlay of wild type (Y98) and mutant (H98). Figures were generated using PyMOL.
Figure 4
Figure 4
Retrospective analysis of the patients with sclerocornea for further ocular abnormalities. A: Axial and sagittal T2-weighted MRI scans of the head and orbits of two affected members 1966 and 1967 (aged 25 and 22 years old) from the MEP54 pedigree. Both patients demonstrate aphakia as depicted by the absence of a dark lens in the anterior part of the eye. In the absence of surgery, the left eye of patient 1966 seems to be phthisical. The axial lengths for 1966 are 10 and 17 mm and 1967 are 19 and 16 mm for the right and left eyes, respectively confirming that there is also microphthalmia. The sagittal section shows that there are no obvious structural abnormalities of the brain. B: Left eye ultrasound scan of patient 1654 from the Mexican pedigree showing an optic disc coloboma (white arrow).

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