Within the human genome are two genes, TSC1 and TSC2, that provide instructions for making proteins that help regulate how cells grow and divide. These genes are best known for their connection to a rare genetic disorder called Tuberous Sclerosis Complex (TSC). In this condition, alterations in either gene disrupt normal cellular control, leading to the growth of noncancerous tumors in many parts of the body.
The Normal Function of TSC1 and TSC2
The TSC1 and TSC2 genes are categorized as tumor suppressor genes. Their primary role is to restrain cell growth and proliferation. The TSC1 gene provides the instructions for producing a protein called hamartin, while the TSC2 gene codes for a protein named tuberin. These two proteins bind to each other inside the cell to form the TSC protein complex.
This protein complex regulates a signaling pathway called the mechanistic target of rapamycin, or mTOR. The mTOR pathway acts like a central command center for the cell, integrating signals from the environment to control cell growth, metabolism, and survival. When nutrients and growth factors are abundant, the mTOR pathway is activated, signaling the cell to grow and divide.
The TSC protein complex (hamartin and tuberin) functions as a brake on this system. It inactivates a small protein called Rheb, which is a direct activator of the mTOR pathway. By keeping Rheb in an “off” state, the TSC complex ensures that the mTOR pathway is not constantly active, thereby applying a necessary check on cell growth and division.
The Role of Mutations in Tuberous Sclerosis Complex
Tuberous Sclerosis Complex arises when a pathogenic mutation occurs in either the TSC1 or the TSC2 gene. A single defective copy of either gene is sufficient to cause the disorder. Such a mutation impairs the formation of the TSC protein complex, which removes the safeguards that keep cellular growth in check.
A mutation in TSC1 or TSC2 acts like a disabled “off” button for the mTOR pathway. Without a functioning TSC protein complex to restrain it, the Rheb protein remains persistently active. This leads to the constant activation of the mTOR pathway, signaling cells to grow and multiply without the normal stop cues.
This hyperactivity is the underlying driver of TSC’s symptoms. The uncontrolled cell growth and division result in the formation of benign tumors, called hamartomas, in various organs. These growths are not cancerous but are composed of abnormal, disorganized mixtures of cells. The systemic nature of mTOR signaling means these hamartomas can appear throughout the body, most commonly affecting the brain, kidneys, heart, lungs, and skin.
Comparing TSC1 and TSC2 Mutations
The TSC1 and TSC2 genes are located on different chromosomes; TSC1 is found on chromosome 9, while TSC2 is on chromosome 16. Pathogenic variants in TSC2 are significantly more common than mutations in TSC1. Studies have identified pathogenic alterations in TSC2 in up to 83% of diagnosed individuals, compared to approximately 17% for TSC1. This disparity is even more pronounced in sporadic cases, where the mutation is new to the individual and not inherited.
Beyond frequency, clinical outcomes often differ depending on the affected gene. Individuals with a TSC2 mutation tend to experience a more severe form of the disorder than those with a TSC1 mutation. This can include a higher likelihood of intellectual disability, more frequent seizures, and more significant kidney involvement. The protein tuberin, produced by TSC2, contains the active domain responsible for inhibiting Rheb, which may explain why its disruption often has more severe consequences.
This is a general tendency, not a strict rule. The severity of Tuberous Sclerosis Complex can vary greatly from person to person, regardless of whether the mutation is in TSC1 or TSC2. Even within the same family, individuals sharing the identical mutation can exhibit a wide range of symptoms and severity, highlighting the influence of other genetic and environmental factors on the disease’s expression.
Genetic Testing and Inheritance
Tuberous Sclerosis Complex follows an autosomal dominant inheritance pattern. This means inheriting one altered copy of either gene from a parent is enough to cause the condition. For a parent who has TSC, there is a 50% chance with each pregnancy that they will pass the mutated gene to their child. This pattern of inheritance accounts for approximately one-third of all TSC cases.
A significant portion of TSC cases, about two-thirds, are not inherited. These are the result of a de novo, or new, mutation in the TSC1 or TSC2 gene. This spontaneous genetic change occurs either in the sperm or egg cell of a parent or very early in embryonic development. In these instances, the parents do not have TSC and typically have no family history of the disorder.
Genetic testing plays a central part in managing TSC. For individuals showing symptoms, a molecular test can confirm a clinical diagnosis by identifying a pathogenic variant in either gene. Finding the specific mutation can be useful for family planning and genetic counseling, allowing at-risk relatives to understand their own status through a straightforward blood test rather than extensive clinical screenings. Confirming the genetic basis of the disorder allows for tailored surveillance and care.