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The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25

Nature Genetics volume 19, pages 140–147 (1998)Cite this article

Abstract

A number of different eye disorders with the presence of early-onset glaucoma as a component of the phenotype have been mapped to human chromosome 6p25. These disorders have been postulated to be either allelic to each other or associated with a cluster of tightly linked genes. We have identified two primary congenital glaucoma (PCG) patients with chromosomal anomalies involving 6p25. In order to identify a gene involved in PCG, the chromosomal breakpoints in a patient with a balanced translocation between 6p25 and 13q22 were cloned. Cloning of the 6p25 breakpoint led to the identification of two candidate genes based on proximity to the breakpoint. One of these, FKHL7, encoding a forkhead transcription factor, is in close proximity to the breakpoint in the balanced translocation patient and is deleted in a second PCG patient with partial 6p monosomy. Furthermore, FKHL7 was found to harbour mutations in patients diagnosed with Rieger anomaly (RA), Axenfeld anomaly (AA) and iris hypoplasia (IH). This study demonstrates that mutations in FKHL7 cause a spectrum of glaucoma phenotypes.

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Figure 1: Localization of the 6p25 and 13q22 breakpoints.
Figure 2: Fine localization of the 6p25 breakpoint of the balanced translocation patient within the physical map of 6p25.
Figure 3: Sequence comparison between the normal chromosomes 6 and 13 and that obtained for the derivative 6 and 13 breakpoint junctions.
Figure 4: Fine localization of the 13q22 breakpoint of the balanced translocation patient within the physical map of 13q22.
Figure 5: Northern-blot analysis of mouse Fkhl7, Gmds and β-actin gene expression.
Figure 6: The pedigree structures of four families with anterior segment defects and mutations in FKHL7.
Figure 7: The genomic DNA sequence flanking the FKHL7 mutations in the families are shown.
Figure 8: Comparison of the forkhead domains of different members of the FKHL-family of genes.

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Acknowledgements

We are grateful to the patients and their families for their participation in this study. We would also like to thank D. Crouch for family recruitment, G. Beck, S. Brown, R. Hockey, L. Law and N. Meyer for technical assistance, S. Fischer for cosmids in the 13q22 region and J. Lin for providing mouse embryos and adult tissues. This work was supported by a grant from the Knight's Templar Eye Foundation (D.Y.N.) and NIH grant R01-EY-10564 (V.C.S. and E.M.S.). We also thank the Roy J. Carver Charitable Trust and the Glaucoma Research Foundation for support.

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Authors and Affiliations

  1. Department of Pediatrics, University of Iowa, Iowa City, 52242, Iowa, USA

    Darryl Y. Nishimura, Ruth E. Swiderski, Charles C. Searby, Shivanand R. Patil, Adam B. Kanis & Val C. Sheffield

  2. Department of Ophthalmology, University of Iowa, Iowa City, 52242, Iowa, USA

    Wallace L. M. Alward & Edwin M. Stone

  3. Howard Hughes Medical Institute, University of Iowa, Iowa City, 52242, Iowa, USA

    Val C. Sheffield

  4. VitreoRetinal Surgery, Minneapolis, 55435, Minnesota, USA

    Steven R. Bennet

  5. Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, 94305 , California, USA

    Julie M. Gastier

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Correspondence to Val C. Sheffield.

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Nishimura, D., Swiderski, R., Alward, W. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 19, 140–147 (1998). https://doi.org/10.1038/493

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