Percin, EF and Ploder, LA and Yu, JJ and Arici, K and Horsford, DJ and Rutherford, A and Bapat, B and Cox, DW and Duncan, AMV and Kalnins, VI and Kocak-Altintas, A and Sowden, JC and Traboulsi, E and Sarfarazi, M and McInnes, RR (2000) Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. NAT GENET , 25 (4) 397 - 401.
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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 identified(1-3), and two others have been inferred by the co-segregation of translocations with the phenotype(4,5). We previously found that mice with ocular retardation (the or-J allele), a microphthalmia phenotype(6), 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 nonsyndromic 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.
|Title:||Human microphthalmia associated with mutations in the retinal homeobox gene CHX10|
|Keywords:||CONGENITAL MICROPHTHALMIA, DNA, EXPRESSION, LOCALIZATION, ZEBRAFISH, PROTEIN, MOUSE, MAPS|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Neurosciences and Mental Health > ICH - Developmental Biology Unit|
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