Tuberous sclerosis complex tumor suppressors

Tuberous Sclerosis Complex (TSC) Tumor Suppressors

Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by the growth of noncancerous (benign) tumors in many parts of the body. These tumors can affect the brain, skin, kidneys, heart, eyes, and lungs, and their impact varies widely among individuals. The condition is caused by mutations in either the TSC1 or TSC2 genes, which encode for the proteins hamartin and tuberin, respectively. These proteins act as tumor suppressors, and their dysfunction leads to the development of TSC-related tumors.

Genetics and Molecular Biology

TSC is an autosomal dominant disorder, meaning that the mutation of only one of the two copies of the gene is sufficient to cause the disorder. The TSC1 gene is located on chromosome 9q34, and the TSC2 gene is on chromosome 16p13.3. Together, hamartin (TSC1) and tuberin (TSC2) form a complex that inhibits the mammalian target of rapamycin (mTOR) pathway, which is crucial for cell growth and proliferation. Mutations that impair the function of either protein lead to unchecked activation of the mTOR pathway, resulting in the abnormal cellular growth seen in TSC.

Clinical Features

The clinical manifestations of TSC can vary significantly from person to person, even among members of the same family. Common features include:

• Angiofibromas: Small, reddish spots on the face, particularly the nose and cheeks.
• Cortical tubers: Brain lesions that can cause seizures, developmental delays, and intellectual disabilities.
• Renal angiomyolipomas: Benign tumors in the kidneys that can lead to bleeding or impaired kidney function.
• Lymphangioleiomyomatosis (LAM): A rare lung condition that affects primarily women, leading to cystic lung destruction.
• Cardiac rhabdomyomas: Heart tumors that are often found in infancy and can cause arrhythmias or obstruction of blood flow.

Diagnosis and Treatment

Diagnosis of TSC is based on a combination of clinical criteria and genetic testing. The presence of two major features or one major feature with two or more minor features suggests a definitive diagnosis. Major features include facial angiofibromas, cortical tubers, renal angiomyolipomas, and cardiac rhabdomyomas, among others. Minor features include dental enamel pits, retinal achromic patch, and confetti skin lesions.

Treatment for TSC is symptomatic and may involve a multidisciplinary team including neurologists, dermatologists, nephrologists, and pulmonologists. Management strategies may include surgical intervention for tumors, medication to control seizures, and mTOR inhibitors like sirolimus or everolimus for tumor growth control.

Research and Future Directions

Research into TSC is focused on understanding the molecular mechanisms underlying the disorder and developing targeted therapies. The discovery of the role of the mTOR pathway in TSC has led to significant advances in treatment, particularly with the use of mTOR inhibitors. Ongoing research aims to improve the efficacy and safety of these treatments and to explore new therapeutic targets.