Townes-Brocks Syndrome More than 55 mutations in the SALL1 gene have been identified in people with Townes-Brocks syndrome. Researchers originally believed that all of these mutations prevented one copy of the gene in each cell from making any protein, resulting in a shortage of SALL1 protein during development. More recently, they found that some mutations lead to the production of an abnormally small version of the SALL1 protein that malfunctions within cells. The malfunctioning protein interferes with normal copies of the SALL1 protein, preventing them from entering the nucleus to regulate gene activity. Scientists suspect that this type of genetic change likely underlies the more severe cases of Townes-Brocks syndrome. Mutations that reduce the amount of SALL1 protein are probably responsible for milder cases of this condition. The SALL1 gene appears to be necessary for the normal development of many different organs and tissues before birth, which helps explain why mutations in this gene can cause the varied birth defects associated with Townes-Brocks syndrome. It is uncertain, however, how SALL1 mutations result in the specific features of this condition including an obstruction of the anal opening (imperforate anus), abnormally shaped ears, and hand malformations.

     The SALL1 gene is part of a group of genes called the SALL family. These genes provide instructions for making proteins that are involved in the formation of tissues and organs during embryonic development. SALL proteins are transcription factors, which means they attach (bind) to specific regions of DNA and help control the activity of particular genes. The exact function of the SALL1 protein is unclear. This protein is made in many tissues, including the kidneys, liver, and fetal and adult brain. Based on the effects of SALL1 mutations, researchers infer that this protein plays an important role in development of the hands (particularly the thumbs), ears, anus, kidneys, and other parts of the body before birth.

The following transcription factors affect gene expression:

• NF-kappaB
• NF-kappaB1
• c-Fos
• E4BP4
• FOXC1

Tissue specificity:

Highest levels in kidney. Lower levels in adult brain (enriched in corpus callosum, lower expression in substantia nigra) and liver.

Developmental stage:

In fetal brain exclusively in neurons of the subependymal region of hypothalamus lateral to the third ventricle.

Molecular Function:

• Rna Polymerase Ii Core Promoter Proximal Region Sequence-Specific Dna Binding
• Transcriptional Repressor Activity, Rna Polymerase Ii Core Promoter Proximal Region Sequence-Specific Binding
• Dna Binding
• Transcription Factor Activity, Sequence-Specific Dna Binding
• Beta-Catenin Binding
• Sequence-Specific Dna Binding
• Transcription Regulatory Region Dna Binding
• Metal Ion Binding

Biological Processes:

• Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
• Ureteric Bud Development
• Branching Involved In Ureteric Bud Morphogenesis
• Kidney Development
• Ventricular Septum Development
• Mesenchymal To Epithelial Transition Involved In Metanephros Morphogenesis
• Transcription, Dna-Templated
• Heart Development
• Gonad Development
• Histone Deacetylation
• Olfactory Nerve Development
• Olfactory Bulb Interneuron Differentiation
• Pituitary Gland Development
• Neurogenesis
• Positive Regulation Of Wnt Signaling Pathway
• Adrenal Gland Development
• Inductive Cell-Cell Signaling
• Somatic Stem Cell Population Maintenance
• Outer Ear Morphogenesis
• Embryonic Digit Morphogenesis
• Negative Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Embryonic Digestive Tract Development
• Limb Development
• Olfactory Bulb Mitral Cell Layer Development
• Kidney Epithelium Development
• Ureteric Bud Invasion