TARDBP

At least 60 mutations in the TARDBP gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. 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 mRNA processing, likely disrupting the production of other proteins. Changes to the TDP-43 protein cause the protein to misfold and form protein clumps (aggregates), which have been found in nerve cells that control muscle movement (motor neurons) in some people with ALS. It is unclear whether TDP-43 protein aggregates causes the nerve cell death that leads to ALS or if they are 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.

Mutations in the TARDBP gene have been found to cause frontotemporal dementia (FTD) without features of amyotrophic lateral sclerosis (ALS, described above). 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 these TARDBP gene mutations result 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.