Anophthalmia and microphthalmia are among the most common ocular birth defects and a significant cause of congenital blindness. The etiology of anophthalmia and microphthalmia is diverse, with multiple genetic mutations associated with each of these conditions, along with potential environmental causes. Based on findings that mutations in the Rx/Rax homeobox genes in mice and fish lead to defects in retinal development and result in animal models of anophthalmia, we screened 75 individuals with anophthalmia and/or microphthalmia for mutations in the human RAX gene. We identified a single proband from this population who is a compound heterozygote for mutations in the RAX gene. This individual carries a truncated allele (Q147X) and a missense mutation (R192Q), both within the DNA-binding homeodomain of the RAX protein, and we have characterized the biochemical properties of these mutations in vitro. Parents and grandparents of the proband were found to be carriers without visible ocular defects, consistent with an autosomal recessive inheritance pattern. This is the first report of genetic mutations in the human RAX gene.

Chibby (Cby) is a conserved component of the Wnt–β-catenin pathway. Cby physically interacts with β-catenin to repress its activation of transcription. To elucidate the function of Cby in vertebrates, we generated Cby−/− mice and found that after 2–3 d of weight loss, the majority of mice die before or around weaning. All Cby−/− mice develop rhinitis and sinusitis. When challenged with Pseudomonas aeruginosa isolates, Cby−/− mice are unable to clear the bacteria from the nasal cavity. Notably, Cby−/− mice exhibit a complete absence of mucociliary transport caused by a marked paucity of motile cilia in the nasal epithelium. Moreover, ultrastructural experiments reveal impaired basal body docking to the apical surface of multiciliated cells. In support of these phenotypes, endogenous Cby protein is localized at the base of cilia. As the phenotypes of Cby−/− mice bear striking similarities to primary ciliary dyskinesia, Cby−/− mice may prove to be a useful model for this condition.

The Rx homeobox gene is a transcriptional regulator indispensable for development of the eye and ventral forebrain. Rx-null homozygotes lack optic pits, which are the earliest ocular structures. To study the roles Rx may play at various stages of eye and brain development, we generated an allelic series at the Rx locus. The targeted allele, Rx(neo), is a severely hypomorphic or null allele. This Rx(neo) allele is converted via FLP-mediated recombination to the Rx(flox) allele, which is phenotypically identical to the wildtype allele. Cre-mediated conversion of Rx(flox) generates the RxDelta2 allele, which, when homozygous, results in an Rx-null phenotype that includes perinatal lethality, anophthalmia, and anterior neural and craniofacial defects. Mice carrying these alleles allow both Cre-mediated inactivation and FLP-mediated activation of Rx gene activity on a conditional basis and will be useful in examining Rx function at different developmental stages and in distinct tissue environments.