MUTATIONS OF THE FORKHEAD WINGED-HELIX GENE, FKHL7, IN PATIENTS WITH AXENFELD-RIEGER ANOMALY/

Genetic linkage, genome mismatch scanning, and analysis of patients wi th alterations of chromosome 6 have indicated that a major locus for d evelopment of the anterior segment of the eye, IRID1, is located at 6p 25. 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 frame shift 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 F KHL7, is expressed in the developing brain, skeletal system, and eye, consistent with FKHL7 having a role in ocular development. However, mu tational screening and genetic-linkage analyses excluded FKHL7 from un derlying the anterior-segment disorders in two IRID1 families with lin kage to 6p25. Our findings demonstrate that, although mutations of FKH IL7 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.