TARDBP

The TARDBP gene provides instructions for making a protein called transactive response DNA binding protein 43 kDa (TDP-43). This protein is found within the cell nucleus in most tissues and is involved in many of the steps of protein production. The TDP-43 protein attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. This protein can also bind to RNA, a chemical cousin of DNA, to ensure the RNA's stability. The TDP-43 gene is involved in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. By cutting and rearranging mRNA molecules in different ways, the TDP-43 protein controls the production of different versions of certain proteins. This process is known as alternative splicing. The TDP-43 can influence various functions of a cell by regulating protein production.

The TARDBP gene is particularly active (expressed) during early development before birth when new tissues are forming. Many of the proteins whose production is influenced by the TDP-43 protein are involved in neuronal and organ development.

amyotrophic lateral sclerosis - caused by mutations in the TARDBP gene

At least 50 mutations in the TARDBP gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive movement problems and muscle wasting. Most mutations change single protein building blocks (amino acids) in the TDP-43 protein. The majority of these changes affect the region of the protein involved in RNA processing, likely disrupting subsequent production of other proteins. Changes to the TDP-43 protein cause the protein to misfold and form protein clumps (aggregates) within nerve cells that control muscle movement (motor neurons). It is unknown how these disruptions cause ALS. Motor neurons die off in people with ALS; however it is unclear whether a buildup of TDP-43 aggregates are the cause of cell death or a byproduct of a dying cell.

Some people with ALS caused by TARDBP gene mutations also develop a condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. It is unclear why some people with TARDBP gene mutations develop FTD and others do not. Individuals who develop both conditions are diagnosed as having ALS-FTD.

other disorders - caused by mutations in the TARDBP gene

Mutations in the TARDBP gene have been found to cause frontotemporal dementia (FTD) without features of amyotrophic lateral sclerosis (ALS). FTD caused by TARDBP gene mutations is characterized by a gradual loss of problem-solving skills and language comprehension. Affected individuals often have changes in personality and behavior that may make it difficult to interact with others in a socially appropriate manner. Most TARDBP gene mutations that cause FTD change single amino acids in the TDP-43 protein. These mutations are thought to affect only part of the protein, leaving other parts of the protein functional. Because the TARDBP gene mutation results in a protein with some residual function, the features of the condition tend to appear later in life, in one's late sixties or early seventies. Some people who inherit the altered TARDBP gene never develop FTD, a situation known as reduced penetrance.