Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions.
OBJECTIVE
Mutations in the forkhead transcription factor gene FOXC1 on 6p25 cause a range of ocular developmental abnormalities, with associated glaucoma. However, FOXC1 mutations have not been found in all similarly affected pedigrees mapping to this interval. This study was undertaken to investigate the potential role of 6p25 rearrangements in causing such phenotypes.


METHODS
Two large families with autosomal dominant iris hypoplasia and early-onset glaucoma, 21 probands with Axenfeld-Rieger phenotypes not attributable to PITX2 mutations, and 7 individuals with documented 6p25 cytogenetic rearrangements, were investigated by genotyping and fluorescence in situ hybridization, with markers and probes from the 6p25 region.


RESULTS
Interstitial 6p25 duplications were present in the unrelated families with iris hypoplasia, whereas an interstitial 6p25 deletion was identified in one Axenfeld-Rieger pedigree. Larger cytogenetic rearrangements, leading to trisomy or monosomy of the 6p25 region, resulted in microcornea and Rieger syndrome phenotypes, respectively. All the rearrangements encompassed FOXC1, increasing or decreasing the number of FOXC1 copies present, and appeared to correlate with the phenotypes observed.


CONCLUSIONS
These findings represent the first example of both interstitial duplications and deletions cosegregating with a human developmental disorder that is attributable to altered dose of transcription factor. The data presented provide additional evidence for the pathogenicity of altered gene dosage of FOXC1 and suggest that a common mechanism is responsible for rearrangements of 6p25.
Lehmann
Ordan J
OJ
Department of Molecular Genetics, Institute of Ophthalmology, London, United Kingdom. ojlehmann@yahoo.com
Ebenezer
Neil D
ND
Ekong
Rosemary
R
Ocaka
Louise
L
Mungall
Andrew J
AJ
Fraser
Scott
S
McGill
James I
JI
Hitchings
Roger A
RA
Khaw
Peng T
PT
Sowden
Jane C
JC
Povey
Sue
S
Walter
Michael A
MA
Bhattacharya
Shomi S
SS
Jordan
Tim
T
D001483:Base Sequence; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D020451:Contig Mapping; D003315:Cornea / Q000002:abnormalities*; D004268:DNA-Binding Proteins; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors; D020440:Gene Duplication; D015321:Gene Rearrangement; D005838:Genotype; D005901:Glaucoma / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007498:Iris / Q000002:abnormalities*; D008297:Male; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D014157:Transcription Factors