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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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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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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DOI: https://doi.org/10.1038/78071
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