Human microphthalmia associated with mutations in the retinal homeobox gene CHX10

Isolated human microphthalmia/anophthalmia, a cause of congenital blindness , is a clinically and genetically heterogeneous developmental disorder char acterized by a small eye and other ocular abnormalities. Three microphthalm ia/anophthalmia loci have been identified(1-3), and two others have been in ferred by the co-segregation of translocations with the phenotype(4,5). We previously found that mice with ocular retardation (the or-J allele), a mic rophthalmia phenotype(6), have a null mutation in the retinal homeobox gene Chx10 (refs 7,8). We report here the mapping of a human microphthalmia loc us on chromosome 14q24.3, the cloning of CHX10 at this locus and the identi fication of recessive CHX10 mutations in two families with nonsyndromic mic rophthalmia (MIM 251600), cataracts and severe abnormalities of the iris. I n affected individuals, a highly conserved arginine residue in the DNA-reco gnition helix of the homeodomain is replaced by glutamine or proline (R200Q and R200P, respectively). Identification of the CHX10 consensus DNA-bindin g sequence (TAATTAGC) allowed us to demonstrate that both mutations severel y disrupt CHX10 function. Human CHX10 is expressed in progenitor cells of t he developing neuroretina and in the inner nuclear layer of the mature reti na. The strong conservation in vertebrates of the CHX10 sequence, pattern o f expression and loss-of-function phenotypes demonstrates the evolutionary importance of the genetic network through which this gene regulates eye dev elopment.