TY - JOUR
T1 - Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly
AU - Mears, Alan J.
AU - Jordan, Tim
AU - Mirzayans, Farideh
AU - Dubois, Stéphane
AU - Kume, Tsutomu
AU - Parlee, Michael
AU - Ritch, Robert
AU - Koop, Benjamin
AU - Kuo, Wen Lin
AU - Collins, Colin
AU - Marshall, Jody
AU - Gould, Douglas B.
AU - Pearce, William
AU - Carlsson, Peter
AU - Enerbäck, Sven
AU - Morissette, Jean
AU - Bhattacharya, Shomi
AU - Hogan, Brigid
AU - Raymond, Vincent
AU - Walter, Michael A.
N1 - Funding Information:
We would like to express our gratitude to the IRID1 families and patients for their cooperation and enthusiasm for this project. We thank the members of the Departments of Medical Genetics and Ophthalmology, University of Alberta, for critical comments on this research and the manuscript. We also would like to thank K. McElligott, J. Schmidt, and S. Christian for their excellent coordination of patient resources. A large number of ophthalmologists participated in this study. We are particularly indebted to Mr. Erich Weber (Austria) for referral of patients. This research was funded by Alberta Heritage Fund for Medical Research (AHFMR) grant EG9400216, the Canadian Genetic Diseases Network, and Medical Research Council of Canada (MRC) grant MT12916 to M.A.W. and, partly, by MRC grant MA13428 to V.R. D.B.G. is a University of Alberta 75th Anniversary Award Scholar. V.R. is a “chercheur-boursier clinicien,” of the Fonds de la Recherche en Santé du Québec. M.A.W. is an MRC and AHFMR scholar. A.J.M. is funded by an AHFMR postdoctoral fellowship. T.J. is supported by Wellsome Trust grant 04361/z/94.
PY - 1998
Y1 - 1998
N2 - 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.
AB - 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.
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U2 - 10.1086/302109
DO - 10.1086/302109
M3 - Article
C2 - 9792859
AN - SCOPUS:0032231330
SN - 0002-9297
VL - 63
SP - 1316
EP - 1328
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -