title: A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye.
abstract: Mutations in the forkhead transcription-factor gene (FOXC1), have been shown to cause defects of the anterior chamber of the eye that are associated with developmental forms of glaucoma. Discovery of these mutations was greatly facilitated by the cloning and characterization of the 6p25 breakpoint in a patient with both congenital glaucoma and a balanced-translocation event involving chromosomes 6 and 13. Here we describe the identification of novel mutations in the FOXC1 gene in patients with anterior-chamber defects of the eye. We have detected nine new mutations (eight of which are novel) in the FOXC1 gene in patients with anterior-chamber eye defects. Of these mutations, five frameshift mutations predict loss of the forkhead domain, as a result of premature termination of translation. Of particular interest is the fact that two families have a duplication of 6p25, involving the FOXC1 gene. These data suggest that both FOXC1 haploinsufficiency and increased gene dosage can cause anterior-chamber defects of the eye.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: D Y
authors.initials: DY
authors.lastname: Nishimura
authors.forename: C C
authors.initials: CC
authors.lastname: Searby
authors.forename: W L
authors.initials: WL
authors.lastname: Alward
authors.forename: D
authors.initials: D
authors.lastname: Walton
authors.forename: J E
authors.initials: JE
authors.lastname: Craig
authors.forename: D A
authors.initials: DA
authors.lastname: Mackey
authors.forename: K
authors.initials: K
authors.lastname: Kawase
authors.forename: A B
authors.initials: AB
authors.lastname: Kanis
authors.forename: S R
authors.initials: SR
authors.lastname: Patil
authors.forename: E M
authors.initials: EM
authors.lastname: Stone
authors.forename: V C
authors.initials: VC
authors.lastname: Sheffield
mesh_terms: D000867:Anterior Chamber / Q000002:abnormalities*; D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005124:Eye Abnormalities / Q000235:genetics*; D051858:Forkhead Transcription Factors; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020161:Physical Chromosome Mapping; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D004247:DNA