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Human microphthalmia associated with mutations in the retinal homeobox gene CHX10

Abstract

Isolated human microphthalmia/anophthalmia, a cause of congenital blindness, is a clinically and genetically heterogeneous developmental disorder characterized by a small eye and other ocular abnormalities. Three microphthalmia/anophthalmia loci have been identified1,2,3, and two others have been inferred by the co-segregation of translocations with the phenotype4,5. We previously found that mice with ocular retardation (the or-J allele), a microphthalmia phenotype6, have a null mutation in the retinal homeobox gene Chx10 (refs 7,8). We report here the mapping of a human microphthalmia locus on chromosome 14q24.3, the cloning of CHX10 at this locus and the identification of recessive CHX10 mutations in two families with non-syndromic microphthalmia (MIM 251600), cataracts and severe abnormalities of the iris. In affected individuals, a highly conserved arginine residue in the DNA-recognition helix of the homeodomain is replaced by glutamine or proline (R200Q and R200P, respectively). Identification of the CHX10 consensus DNA-binding sequence (TAATTAGC) allowed us to demonstrate that both mutations severely disrupt CHX10 function. Human CHX10 is expressed in progenitor cells of the developing neuroretina and in the inner nuclear layer of the mature retina. The strong conservation in vertebrates of the CHX10 sequence, pattern of expression and loss-of-function phenotypes demonstrates the evolutionary importance of the genetic network through which this gene regulates eye development.

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Figure 1: The human CHX10 gene and cDNA structure.
Figure 2: CHX10 is abundantly expressed in the inner nuclear layer of human adult retina, and in retinal neuroblasts during eye development.
Figure 3: Pedigrees of two families with autosomal recessive microphthalmia.
Figure 4: Clinical presentation of patients with CHX10 mutations.
Figure 5: Two missense homeo-domain mutations in Arg200 of the CHX10 protein reduce binding to the CHX10 DNA consensus binding sequence.

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References

  1. Graham, C.A., Redmond, R.M. & Nevin, N.C. X-linked clinical anophthalmos. Localization of the gene to Xq27–Xq28. Ophthal. Paediatr. Genet. 12, 43–48 (1991).

    Article  CAS  Google Scholar 

  2. Othman, M.I. et al. Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11. Am. J. Hum. Genet. 63, 1411–1418 (1998).

    Article  CAS  Google Scholar 

  3. Bessant, D.A. et al. A locus for autosomal recessive congenital microphthalmia maps to chromosome 14q32. Am. J. Hum. Genet. 62, 1113–1116 (1998).

    Article  CAS  Google Scholar 

  4. Al-Gazali, L.I. et al. Two 46,XX,t(X;Y) females with linear skin defects and congenital microphthalmia: a new syndrome at Xp22.3. J. Med. Genet. 27, 59–63 (1990).

    Article  CAS  Google Scholar 

  5. Yokoyama, Y., Narahara, K., Tsuji, K., Ninomiya, S. & Senio, Y. Autosomal dominant congenital cataract and microphthalmia associated with a familial t(2;16) translocation. Hum. Genet. 90, 177–178 (1992).

    Article  CAS  Google Scholar 

  6. Truslove, G.M. A gene causing ocular retardation in the mouse. J. Embryol. Exp. Morph. 10, 652–660 (1962).

    CAS  PubMed  Google Scholar 

  7. Burmeister, M. et al. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nature Genet. 12, 376–384 (1996).

    Article  CAS  Google Scholar 

  8. Liu, I.S.-C. et al. Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13, 377–393 (1994).

    Article  CAS  Google Scholar 

  9. Belecky-Adams, T. et al. Prox-1, Pax6 and Chx10 homeobox gene expression correlates with phenotypic fate of retinal precursor cells. Invest. Ophthalmol. Vis. Sci. 38, 1293–1303 (1997).

    CAS  PubMed  Google Scholar 

  10. Barabino, S.M., Spada, F., Cotelli, F. & Boncinelli, E. Inactivation of the zebrafish homologue of Chx10 by antisense oligonucleotides causes eye malformations similar to the ocular retardation phenotype. Mech. Dev. 63, 133–143 (1997).

    Article  CAS  Google Scholar 

  11. Chen, C.-M.A. & Cepko, C.L. Expression of Chx10 and Chx10-1 in the developing chick retina. Mech. Dev. 90, 293–297 (2000).

    Article  CAS  Google Scholar 

  12. Passini, M.A., Levine, E.M., Canger, A.K., Raymond, P.A. & Schechter, N. Vsx-1 and Vsx-2: differential expression of two paired-like homeobox genes during zebrafish and goldfish retinogenesis. J. Comp. Neurol. 388, 495–505 (1997).

    Article  CAS  Google Scholar 

  13. Cooper, D. & Krawczak, M. The mutational spectrum of single basepair substitutions causing human genetic disease: patterns and predictions. Hum. Genet. 85, 55–74 (1990).

    Article  CAS  Google Scholar 

  14. Wilson, D.S., Guenther, B., Desplan, C. & Kiriyan, J. High resolution crystal structure of a paired (pax) class cooperative homeodomain dimer on DNA. Cell 82, 709–719 (1995).

    Article  CAS  Google Scholar 

  15. Pollock, R. & Treisman, R. A sensitive method for the determination of protein-DNA binding specificities. Nucleic Acids Res. 18, 6197–6204 (1990).

    Article  CAS  Google Scholar 

  16. Zarkower, D. & Hodgkin, J. Zinc fingers in sex determination: only one of the two C. elegans Tra-1 proteins binds DNA in vitro. Nucleic Acids Res. 21, 3691–3698 (1993).

    Article  CAS  Google Scholar 

  17. Wilson, D., Sheng, G., Lecutt, T., Dostatni, N. & Desplan, C. Cooperative dimerization of paired class homeodomains on DNA. Genes Dev. 7, 2120–2134 (1993).

    Article  CAS  Google Scholar 

  18. Duboule, D. (ed.) Guidebook to the Homeobox Genes (Oxford University Press, Toronto, 1994).

    Google Scholar 

  19. Dattani, M.T. et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nature Genet. 19, 125–133 (1998).

    Article  CAS  Google Scholar 

  20. Bone-Larson, C. et al. Partial rescue of the ocular retardation phenotype by genetic modifiers. J. Neurobiol. 42, 232–247 (2000).

    Article  CAS  Google Scholar 

  21. Isenberg, S.J. Physical and refractive characteristics of the eye at birth and during infancy. in The Eye in Infancy (ed. Isenberg, S.J.) 36–51 (C.V. Mosby, St. Louis, 1994).

    Google Scholar 

  22. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  23. Duncan, A.M.V., Chow, W. & Robinson, G.H. Localization of the human 75 Kd Fe-S protein of NADH-Coenzyme Q Reductase gene to 2q33–34. Cytogenet. Cell Genet. 60, 212–213 (1992).

    Article  CAS  Google Scholar 

  24. Dib, C. et al. A comprehensive genetic map of the human genome based on 5264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  Google Scholar 

  25. Breitschopf, H., Suchanek, G., Gould, R.M., Colman, D.R. & Lassmann, H. In situ hybridization with digoxigenin-labeled probes: sensitive and reliable detection method applied to myelinating rat brain. Acta Neuropathol. (Berl) 84, 581–587 (1992).

    Article  CAS  Google Scholar 

  26. Bascom, R.A., Liu, L., Heckenlively, J.R., Stone, E.M. & McInnes, R.R. Mutation analysis of the ROM1 gene in retinitis pigmentosa. Hum. Mol. Genet. 4, 1895–1902 (1995).

    Article  CAS  Google Scholar 

  27. Cormack, B. Mutagenesis of cloned DNA. in Current Protocols in Molecular Biology (eds Ausubel, F.M. et al.) 8.5.7–8.5.9 (John Wiley & Sons, Boston, 1999).

    Google Scholar 

  28. Pollock, R.M. DNA-protein interactions. in Current Protocols in Molecular Biology (eds Ausubel, F.M. et al.) 12.11.11–12.11.17 (John Wiley & Sons, Boston, 1999).

    Google Scholar 

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Acknowledgements

We thank the participating members of the families; M. Hankin for the description of the iris of Chx10or-J/or-J mice; J. Nathans for the adult human retina λgt10 cDNA library; D. Zarkower for the PT7tagN vector and advice; M. Ozguc for facilitating DNA extraction; W. Shih and L. Collins for technical assistance; and L. Wong. This study was supported by grants from the TUBITAK, Ankara, Turkey to E.F.P., the MRC UK to J.C.S., and from The Medical Research Council of Canada, The Canadian Genetic Disease Network and The RP Eye Research Foundation of Canada to R.R.M. D.J.H. is the recipient of a FFB Canada/MRC doctoral research award, and A.R. is a Fight for Sight Research Student. R.R.M. is an International Research Scholar of the Howard Hughes Medical Institute.

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Correspondence to Mansoor Sarfarazi or Roderick R. McInnes.

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Ferda Percin, E., Ploder, L., Yu, J. et al. Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nat Genet 25, 397–401 (2000). https://doi.org/10.1038/78071

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