Ocular Coloboma is a genetic disorder characterized, phenotypically, by an abnormal appearance of the iris. When the PAX6 gene (responsible for the development of the precursor lens of the eye) is mutated, it can cause Ocular Coloboma by not allowing for the effective closure of the embryonic fissure of the optic cup (O’Neill et al 1986). The PAX6 gene is located on the P arm of the eleventh chromosome (11p13) and is a member of a complex of proteins called the paired box gene family (OMIM 2013).
PAX6 is responsible for many different things during fetal development having to do with the brain, spinal cord, and pancreas. Ocular Coloboma can also occur with a variety of other disorders, such as mental retardation, absence of the corpus callosum, etc., due to the volume of neural tissues PAX6 is responsible for developing (OMIM 2013).
The cause of Ocular Coloboma is not well understood. It most likely an autosomal dominant mutation of the PAX6 gene, with some research supporting autosomal recessive inheritance. There is also some research supporting a dominant-negative mutation. A dominant-negative mutation is a gain-of-function mutation and is extremely rare (OMIM 2013). These types of mutations will usually result in some form of cancer, and the particular one that causes Ocular Coloboma occurs in approximately one of 10,000 people.
PAX6 functions to target genes through a paired-type DNA-binding domain, which is comprised of two binding subdomains; one is an N-terminal subdomain and the other is a C-terminal subdomain. In humans, the PAX6 gene is responsible for two alternatively spliced isoforms, each with a unique composition like that of the paired domain (OMIM 2013). This paired-type binding domain allows for exon 5a to work as a sort of molecular switch, with certain genes it is set to target (OMIM 2013).
The cloning technique that was used to determine this function utilized an insert of fourteen amino acids into the N-terminal subdomain. Exon 5a encodes for these amino acids (OMIM 2013). This insert causes changes in the DNA binding activity; the N-terminal subdomain can no longer bind and the C-terminal subdomain gains the ability to bind. Changing the function of the binding sites with the insert shows how exon 5a can switch them “on” or “off” (OMIM 2013).
Mice, with the disorder “small eye” serve as an animal model for the PAX6 gene (OMIM). This disorder is located on the second chromosome and is similar to one of the forms of aniridia, which is another disorder caused by a mutation of the PAX6 gene. “Small eye” is located on a different chromosome than other PAX6 disorders in humans; this is due to the homology of chromosome two in mice and the p arm of chromosome 11 in humans (OMIM 2013).
Materials and Methods
OMIM-Online Mendelian Inheritance in Man- http://omim.org/
Homo sapiens PAX6 (PAX6) gene, partial coding sequence
Organism: Homo Sapien
Length: 447 Bp...