PAX3

At least one PAX3 gene variant (also known as a mutation) has been identified in individuals with craniofacial-deafness-hand syndrome, a condition characterized by distinctive facial features, profound hearing loss, and abnormalities of the hand muscles that can restrict movement. The variant replaces a single protein building block (amino acid) called asparagine with another amino acid called lysine at position 47 in the PAX3 protein (written as Asn47Lys or N47K). This variant appears to affect the ability of the PAX3 protein to bind to DNA. As a result, the PAX3 protein cannot control the activity of other genes and cannot direct the neural crest cells to form specialized tissues. A lack of specialization of neural crest cells leads to the impaired growth of craniofacial bones, nerve tissue, and muscles seen in craniofacial-deafness-hand syndrome.

PAX3 gene variants have been identified in people with Waardenburg syndrome, a group of genetic conditions that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Specifically, PAX3 gene variants can cause Waardenburg syndrome types I and III.

Some of these variants change single amino acids in the PAX3 protein. Other variants lead to an abnormally small version of the PAX3 protein. Researchers believe that all PAX3 gene variants have the same effect: they prevent the PAX3 protein from binding to DNA and regulating the activity of other genes. As a result, melanocytes do not develop in certain areas of the skin, hair, eyes, and inner ear, leading to hearing loss and the patchy loss of pigmentation that are characteristic features of Waardenburg syndrome. Additionally, loss of PAX3 protein function disrupts development of certain bones and muscles, producing abnormalities of the arms and hands in people with Waardenburg syndrome type III.

Rearrangements of genetic material involving the PAX3 gene are associated with a cancer of muscle tissue called alveolar rhabdomyosarcoma, which typically affects adolescents and young adults. This genetic change is somatic, which means that it is not inherited and occurs only in the cells that give rise to cancer. The rearrangements cause the PAX3 gene to be fused with another gene, most commonly the FOXO1A gene (also called FKHR) on chromosome 13. The protein produced from the fused PAX3-FOXO1A gene has an increased ability to activate genes involved in myogenesis and can prevent cell death. As a result, muscle cell growth becomes uncontrolled, which can lead to this cancer of muscle tissue.

Somatic rearrangements involving the PAX3 gene are also associated with a cancer of the nasal passages and sinuses called biphenotypic sinonasal sarcoma. This type of cancer usually occurs in adulthood and affects women more often than men. The genetic rearrangements involved in biphenotypic sinonasal sarcoma fuse the PAX3 gene with another gene, most commonly the MAML3 gene on chromosome 4. The protein produced from the fusion gene is overactive and turns on genes involved in the development of structures in the nasal passages and sinuses abnormally. As a result, cells in these structures can grow without control, forming a tumor.