Waardenburg Syndrome Due to PAX3 Mutations
Waardenburg Syndrome was discovered in 1951 by a Dutch opthamologist, Petrus Johannes Waardenburg. He observed that often people with two different colored eyes also had hearing problems. This disease is now believed to be due to a genetic mutation that is inherited in an autosomal-dominant pattern, with parents with the disease having a fifty-percent chance of passing it on to their children. Today, almost fifty years after Waardenburg made his initial observations, much has been learned about this rare disease.
There are many characteristic signs that indicate someone has Waardenburg Syndrome, or WS. The variety and severity of characteristics that these people display, however, is extremely vast. First, it affects the hearing. Over two percent of deafness at birth is due to Waardenburg Syndrome (Morell et al, 1997). However, there is a vast range of hearing impairments. Some people lose their hearing in both ears, others in just one, and still others have just a slight loss or even normal hearing. The second way it affects the body is through pigment disorders. Some people with this disease have two different colored eyes. One is usually brown and the other blue, or sometimes brown and blue splotches are mixed in the same eye. A white forelock of hair, premature graying and white patches of skin are other pigment abnormalities. The third characteristic is lateral displacement of the inner canthi, or "dystopia canthorum." This means that there is a wide space between the eyes. Connected eyebrows, a low hairline, and a broad nasal root are other signs of this disorder. Due to the wide variety of symptoms and the varying severity people with WS display, it is often hard to diagnose.
There are four sub-types of Waardenburg syndrome. Two of these, Type 1 (WS1) and Type 3 (WS3) are caused by mutations on the PAX3 gene on chromosome 2q35. The other types are due to various mutations on chromosome three, twenty, and thirteen. Type 1 WS is characterized by a wide space between the inner corners of the eyes which is usually seen in almost all WS1 cases (Smith et al, 1998). Type 3, also called Klein-Waardenburg syndrome has the characteristic symptoms of WS1 and in addition may display microcephaly, mental retardation, and skeletal abnormalities (Lalwani et al, 1995). WS Type 3 is a rare condition and may be due to the homozygous form of the mutation, although it is not always the case.
The PAX3 gene, as mentioned above, is the gene responsible for Types 1 and 3 of this disorder. This locus was discovered through linkage analysis, mutation studies, and specifically comparative mapping in mice (Reynolds et al, 1996). Splotchy coloring in the coat of mice prompted scientists to believe that the same gene may be causing WS in humans. Since mice are easier to study, scientists located the splotchy-colored coat gene mutation to be located on the pax3 gene. The...