Cataracts can be associated with a variety of diseases in humans and other mammalian species or they can be present as the only disease manifestation. Since cataracts are known to have genetic heterogeneity, it has been difficult to isolate a congenital cataract gene. Therefore, animal mutant models serve as an excellent source for the isolation of congenital cataract genes. The X-linked cataract (Xcat) mouse is one such model for inherited congenital cataracts (Stambolian et al. 1990). Xcat mice are characterized by a total lens opacity in hemizygous males and homozygous females (Favor and Pretsch 1987). Histological examination of the lens in the mutant mouse has shown structural abnormalities of the primary lens fibers as early as embryonic day 14 (Grimes et al. 1993). Xcat appears to be an animal model for the human Nance-Horan Syndrome because of the phenotypic similarity between the human and mouse cataracts and because of the similar location on homologous segments of the X Chromosome (Chr).
Previously, the Xcat gene had been mapped to the mouse Chr X in the distal region between the proteolipid protein, Plp, and amelogenin, Amg, loci. It was found to be closely linked to the loci DXWas31, DXPas18, DXMit15, DXMit20, and Grpr with no recombinations between these markers and Xcat (Stambolian et al. 1994). Several candidate genes including Grpr, Cxn33, and Pdhal map in this region of the X Chr.
Grpr, the gene for gastrin-releasing peptide, is a receptor (Maslen and Boyd 1993) that binds to gastrin-releasing peptide (GRP), which is widely distributed and functions as a neurotransmitter (Spindel 1986), growth factor (Wharton et al. 1978), and paracrine hormone (Walsh et al. 1979).
Cxn33, the gene for a gap junction protein, is a member of the connexin family (Hsieh et al. 1991). The protein is assembled in the plasma membrane of adjacent cells to form intercellular channels to transfer ions and small molecules and also has a role in the coordination of contraction in cardiac muscle and synapses between neurons. Mouse Cxn33 and Cxn32 are the only two connexins that have been mapped to the X Chr (Haefliger et al. 1992). Cxn32 is the gene mutated in X-linked dominant Charcot-Marie-Tooth disease (Fairweather et al. 1994). From its map position and its physiological role in intercellular channels of fiber membranes, Cxn33 is considered a good candidate for the Xcat gene.
Pdhal is the gene for pyruvate dehydrogenase E1 ~ subunit and plays a key role in the function of the PDH (pyrnvate dehydrogenase) complex that is composed of three enzymes, pyruvate