SALL1

At least 75 mutations in the SALL1 gene have been identified in people with Townes-Brocks syndrome, which is typically characterized by a malformation of the anal opening (imperforate anus), abnormally shaped ears, and hand malformations. It is uncertain how these mutations result in the specific features of the condition.

Most SALL1 gene mutations involved in this disorder lead to the production of an abnormally short version of the SALL1 protein that malfunctions within cells. The malfunctioning protein is thought to interfere with normal copies of the SALL1 protein, which are produced from the other copy of the SALL1 gene that does not have a mutation. This interference prevents the normal proteins from entering the nucleus to regulate gene activity. The malfunctioning protein may also interact with other proteins, disrupting their function. For example, some research indicates that the abnormally short SALL1 protein interferes with proteins that control the formation of cellular structures called cilia. Cilia are microscopic, finger-like projections that stick out from the surface of cells and participate in signaling pathways that transmit information within and between cells. Cilia are important for the structure and function of many types of cells and the normal development of several tissues. Abnormalities in cilia can disrupt important chemical signaling pathways during development and may contribute to the features of Townes-Brocks syndrome.

Other, less-common SALL1 gene mutations prevent the gene from making protein; this reduces by half the amount of SALL1 protein produced in cells. Some studies suggest that mutations that reduce the amount of SALL1 protein are responsible for milder cases of Townes-Brocks syndrome, and mutations that result in an abnormally short, malfunctioning SALL1 protein underlie the more severe cases of the condition. However, other studies do not find the same correlation.

A shortage of functioning SALL1 protein, due to either type of mutation, likely impairs the regulation of genes that direct the development of many different organs and tissues before birth. Abnormal development before birth due to unusual gene activity leads to the varied birth defects associated with Townes-Brocks syndrome.

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