Mutations of the Forkhead/Winged-Helix Gene, FKHL7, in Patients with Axenfeld-Rieger Anomaly

• Published in: American journal of human genetics Vol. 63; no. 5; pp. 1316 - 1328
• Main Authors: Mears, Alan J., Jordan, Tim, Mirzayans, Farideh, Dubois, Stéphane, Kume, Tsutomu, Parlee, Michael, Ritch, Robert, Koop, Benjamin, Kuo, Wen-Lin, Collins, Colin, Marshall, Jody, Gould, Douglas B., Pearce, William, Carlsson, Peter, Enerbäck, Sven, Morissette, Jean, Bhattacharya, Shomi, Hogan, Brigid, Raymond, Vincent, Walter, Michael A.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.11.1998; University of Chicago Press
• Subjects: Amino Acid Sequence; Animals; Axenfeld-Rieger anomaly; Base Sequence; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 6; Diseases of cornea, anterior segment and sclera; DNA Primers; DNA-Binding Proteins - genetics; Exons; Eye Abnormalities - genetics; Female; Forkhead; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Genetic Markers; Glaucoma; Glaucoma - genetics; Humans; Iridogoniodysgenesis; Iris - abnormalities; Male; Medical sciences; Mice; Molecular Sequence Data; Ocular defects; Ophthalmology; Phenotype; Polymerase Chain Reaction; Transcription factor; Transcription Factors - genetics; Glaucoma; Iridogoniodysgenesis; Forkhead; Axenfeld-Rieger anomaly; Transcription factor; Ocular defects; Human; Linkage; Family study; Chromosome C6; Congenital disease; Genetic determinism; Eye disease; Axenfeld syndrome; Gene; Malformation; Glaucoma (eye); Mutation; Locus; Anterior segment disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302109

Genetic linkage, genome mismatch scanning, and analysis of patients with alterations of chromosome 6 have indicated that a major locus for development of the anterior segment of the eye, IRID1, is located at 6p25. Abnormalities of this locus lead to glaucoma. FKHL7 (also called “ FREAC3”), a member of the forkhead/winged-helix transcription-factor family, has also been mapped to 6p25. DNA sequencing of FKHL7 in five IRID1 families and 16 sporadic patients with anterior-segment defects revealed three mutations: a 10-bp deletion predicted to cause a frameshift and premature protein truncation prior to the FKHL7 forkhead DNA-binding domain, as well as two missense mutations of conserved amino acids within the FKHL7 forkhead domain. Mf1, the murine homologue of FKHL7, is expressed in the developing brain, skeletal system, and eye, consistent with FKHL7 having a role in ocular development. However, mutational screening and genetic-linkage analyses excluded FKHL7 from underlying the anterior-segment disorders in two IRID1 families with linkage to 6p25. Our findings demonstrate that, although mutations of FKHL7 result in anterior-segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is also located at 6p25.