2.1. Lymphangioleiomyomatosis

Mutations in the TSC1 gene can cause a disorder called lymphangioleiomyomatosis (LAM), although mutations in the TSC2 gene appear to be responsible for most cases of this disorder. This destructive lung disease is caused by the abnormal overgrowth of smooth muscle-like tissue in the lungs. It occurs almost exclusively in women, causing coughing, shortness of breath, chest pain, and lung collapse.

LAM can occur alone (isolated or sporadic LAM) or in combination with a condition called tuberous sclerosis complex (described below). Researchers suggest that sporadic LAM can be caused by a random mutation in the TSC1 gene that occurs very early in development. As a result, some of the body's cells have a normal version of the gene, while others have the mutated version. This situation is called mosaicism. When a mutation occurs in the other copy of the TSC1 gene in certain cells during a woman's lifetime (a somatic mutation), she may develop LAM.

2.2. Tuberous sclerosis complex

More than 400 mutations in the TSC1 gene have been identified in individuals with tuberous sclerosis complex, a condition characterized by developmental problems and the growth of noncancerous tumors in many parts of the body. Most of these mutations involve either small deletions or insertions of DNA in the TSC1 gene. Some mutations create a premature stop signal in the instructions for making hamartin.

People with TSC1-related tuberous sclerosis complex are born with one mutated copy of the TSC1 gene in each cell. This mutation prevents the cell from making functional hamartin from that copy of the gene. However, enough hamartin is usually produced from the other, normal copy of the TSC1 gene to regulate cell growth effectively. For some types of tumors to develop, a second mutation involving the other copy of the gene must occur in certain cells during a person's lifetime.

When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of hamartin also interferes with the normal development of certain cells. In people with TSC1-related tuberous sclerosis complex, a second TSC1 gene mutation typically occurs in multiple cells over an affected person's lifetime. The loss of hamartin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues.

2.3. Other disorders

Inherited mutations in the TSC1 gene can cause a disorder known as focal cortical dysplasia of Taylor balloon cell type. This disorder involves malformations of the cerebrum, the large, frontal part of the brain that is responsible for thinking and learning. Focal cortical dysplasia causes severe recurrent seizures (epilepsy) in affected individuals.

Cholangiocarcinoma