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Homozygous FOXE3 Mutations Cause Non

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  • 8/6/2019 Homozygous FOXE3 Mutations Cause Non

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    Homozygous FOXE3 mutations cause non-syndromic,

    bilateral, total sclerocornea, aphakia, microphthalmia and

    optic disc coloboma.

    Ali M, Buentello-Volante B, McKibbin M, Rocha-Medina JA, Fernandez-Fuentes N, Koga-Nakamura W,Ashiq A, Khan K, Booth AP, Williams G, Raashid Y, Jafri H, Rice A, Inglehearn CF, Zenteno JC.

    Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK. [email protected]

    Abstract

    PURPOSE: To investigate the genetic basis of recessively-inherited congenital, non syndromic, bilateral, totalsclerocornea 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 andmagnetic 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 wasconfirmed with polymorphic microsatellite markers. Candidate genes weresequenced.

    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 onchromosome 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 thepreviously 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 theMexican 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 segmentabnormalities 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 ofnon-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 theFOXE3 heterozygotes described suggests that genetic background and environmental factors plays a role in the

    penetrance of the mutant allele.

    http://www.ncbi.nlm.nih.gov/pubmed/20664696


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