Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma

[摘要] Purpose: To investigate the geneticbasis of recessively-inherited congenital, non syndromic, bilateral,total sclerocornea in two consanguineous pedigrees, one from the Punjabprovince of Pakistan and the other from the Tlaxcala province ofMexico. Methods: Ophthalmic examinations wereconducted on each family member to confirm their diagnosis and magneticresonance imaging (MRI) or ultrasonography of the eyes was performed onsome family members. Genomic DNA was analyzed by homozygosity mappingusing the Affymetrix 6.0 SNP array and linkage was confirmed withpolymorphic microsatellite markers. Candidate genes were sequenced. Results: A diagnosis of autosomalrecessive sclerocornea was established for 7 members of the Pakistaniand 8 members of the Mexican pedigrees. In the Pakistani family weestablished linkage to a region on chromosome 1p that containedForkhead Box E3 (FOXE3), a strong candidate gene since FOXE3mutations had previously been associated with various anterior segmentabnormalities. Sequencing FOXE3 identified the previouslyreported nonsense mutation, c.720C>A, p.C240X, in the Pakistanipedigree and a novel missense mutation which disrupts an evolutionarilyconserved residue in the forkhead domain, c.292T>C, p.Y98H, in theMexican pedigree. Individuals with heterozygous mutations had no ocularabnormalities. MRI or ultrasonography confirmed that the patients withsclerocornea were also aphakic, had microphthalmia and some had opticdisc coloboma. Conclusions: This is the fourth reportdetailing homozygous FOXE3 mutations causing anterior segmentabnormalities in human patients. Previous papers have emphasizedaphakia and microphthalmia as the primary phenotype, but we find thatthe initial diagnosis – and perhaps the only one possible in a ruralsetting – is one of non-syndromic, bilateral, total sclerocornea.Dominantly inherited anterior segment defects have also been noted inassociation with heterozygous FOXE3 mutations. However theabsence of any abnormalities in the FOXE3 heterozygotesdescribed suggests that genetic background and environmental factorsplays a role in the penetrance of the mutant allele.

[学科分类] 生物化学/生物物理