Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma.
OBJECTIVE
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.
Ali
Manir
M
Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK. medma@leeds.ac.uk
Buentello-Volante
Beatriz
B
McKibbin
Martin
M
Rocha-Medina
J Alberto
JA
Fernandez-Fuentes
Narcis
N
Koga-Nakamura
Wilson
W
Ashiq
Aruna
A
Khan
Kamron
K
Booth
Adam P
AP
Williams
Grange
G
Raashid
Yasmin
Y
Jafri
Hussain
H
Rice
Aine
A
Inglehearn
Chris F
CF
Zenteno
Juan Carlos
JC
D000595:Amino Acid Sequence; D001035:Aphakia / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D003103:Coloboma / Q000150:complications / Q000235:genetics*; D003315:Cornea / Q000002:abnormalities*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008800:Mexico; D008850:Microphthalmos / Q000150:complications / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009898:Optic Disk / Q000002:abnormalities*; D010154:Pakistan; D010375:Pedigree; D013577:Syndrome
C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors