TSC2

TSC2 gene variants (also known as mutations) cause most cases of a disorder called lymphangioleiomyomatosis (LAM). This destructive lung disease is characterized 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 is caused by a random variant in the TSC2 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 altered version. This situation is called mosaicism. When a variant occurs in the other copy of the TSC2 gene in certain cells during a woman's lifetime (a somatic variant), she may develop LAM.

More than a thousand variants in the TSC2 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 variants insert or delete a small number of DNA building blocks (base pairs) in the TSC2 gene. Other variants change a single base pair in the TSC2 gene or create a premature stop signal in the instructions for making tuberin.

People with TSC2-related tuberous sclerosis complex are born with one altered copy of the TSC2 gene in each cell. A TSC2 gene variant prevents the cell from making functional tuberin from that copy of the gene. Enough tuberin is usually produced from the other, normal copy of the TSC2 gene to regulate cell growth effectively. For some types of tumors to develop, a second variant involving the other copy of the gene must occur in certain cells during a person's lifetime.

When both copies of the TSC2 gene are altered in a particular cell, that cell cannot produce any functional tuberin. The loss of this protein allows the cell to grow and divide in an uncontrolled way to form a tumor. A shortage of tuberin also interferes with the normal development of certain cells. In people with TSC2-related tuberous sclerosis complex, a second TSC2 gene variant typically occurs in multiple cells over an affected person's lifetime. The loss of tuberin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues, leading to the signs and symptoms of tuberous sclerosis complex.