The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma.
OBJECTIVE
Primary congenital glaucoma (PCG) is an autosomal recessive disorder that has been linked to CYP1B1 mutations. This study was conducted to explore the role of FOXC1, which is involved in anterior segment dysgenesis, in PCG.


METHODS
An earlier screening for CYP1B1 in a clinically well-characterized PCG cohort (n = 301) revealed cases that were either homozygous (n = 73), compound heterozygous (n = 18), or heterozygous (n = 41) for the mutant allele, whereas the remaining (n = 169) did not harbor any mutation. Hence, FOXC1 was screened in 210 PCG cases who were either heterozygous (n = 41) or did not harbor any CYP1B1 mutation (n = 169), along with ethnically matched normal control subjects (n = 157) by resequencing the entire coding region.


RESULTS
Two heterozygous missense (H128R and C135Y) and three frame shift mutations (g.1086delC, g.1155del9bp, and g.1947dup25bp) were observed in FOXC1 in 5 (2.38%) of 210 cases. The missense mutations had a de novo origin in two sporadic cases, whereas the FOXC1 deletions were seen in two cases that were also heterozygous for the CYP1B1 allele (R368H). The parents of the proband with g.1086delC were heterozygous for either the FOXC1 or CYP1B1 alleles. The unaffected mother of the proband with the g.1155del9bp was heterozygous for both the FOXC1 and CYP1B1 alleles; the father harbored only the FOXC1 allele. Familial segregation of the g.1947dup25bp could not be performed because of the unavailability of DNA from one parent. Except for the g.1155del9bp (0.95% normal chromosomes), all the other variations were absent in the control subjects.


CONCLUSIONS
The present study indicates a limited role of FOXC1 in PCG pathogenesis.
Chakrabarti
Subhabrata
S
Hyderabad Eye Research Foundation, Hyderabad, India. subho@lvpei.org
Kaur
Kiranpreet
K
Rao
Kollu Nageswara
KN
Mandal
Anil K
AK
Kaur
Inderjeet
I
Parikh
Rajul S
RS
Thomas
Ravi
R
D017668:Age of Onset; D000869:Anterior Eye Segment / Q000002:abnormalities; D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D016368:Frameshift Mutation; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction
D017931:DNA Primers; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1