Identification of the IRXB gene cluster as candidate genes in severe dysgenesis of the ocular anterior segment.
OBJECTIVE
Anterior segment ocular dysgenesis (ASOD) is a broad heterogeneous group of diseases detectable at the clinical and molecular level. In a patient with bilateral congenital ASOD including aniridia and aphakia, a complex chromosomal rearrangement, inv(2)(p22.3q12.1)t(2;16)(q12.1;q12.2), was characterized at the molecular level, to identify candidate genes implicated in ASOD.


METHODS
After negative sequencing of the PAX6, FOXC1, and PITX2 genes, we used fluorescence in situ hybridization (FISH) and Southern blot analysis to characterize the chromosomal breakpoints. Candidate genes were selected, and in situ tissue expression analysis was performed on human fetuses and embryos.


RESULTS
Molecular analyses showed that the 16q12.2 breakpoint in this rearrangement occurs in a 625-bp region centromeric to the IRX3 gene, which belongs to the IRXB cluster. In situ hybridization expression studies showed that during early human embryonic development, the IRX3 gene is expressed in the anterior segment of the eye. Of interest, it has been shown previously that a highly conserved noncoding region (HCNCR) is located 300 kb centromeric to the IRX3 gene and induces, in a murine transgenic assay, an expression pattern fitting that of the IRX3 gene.


CONCLUSIONS
The authors propose that the 16q12.2 breakpoint of this complex translocation is causally related to the ocular anterior segment dysgenesis observed in this patient. This translocation is assumed to separate the HCNCR from the IRXB cluster genes, thus deregulating the IRXB cluster and leading to the ASOD observed by a positional effect.
Chaabouni
Myriam
M
Service de Cytogénétique, INSERM, Paris, France. chaabouni_myriam@yahoo.fr
Etchevers
Heather
H
De Blois
Marie Christine
MC
Calvas
Patrick
P
Waill-Perrier
Marie Christine
MC
Vekemans
Michel
M
Romana
Serge Pierrick
SP
D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000502:physiology*; D019457:Chromosome Breakage; D002885:Chromosomes, Human, Pair 16; D002889:Chromosomes, Human, Pair 2; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D018398:Homeodomain Proteins; C501598:IRX3 protein, human; D014157:Transcription Factors