The Story of TSC1

The gene whose mutation causes potato-like protrusions.

In the late 1800s, a teenage girl with curious symptoms visited French neurologist Desire­ Magloire Bourneville. She had been having seizures since birth and her speech and thought processes were delayed. A clump of small raised papules covered her nose, cheeks, and forehead; and many round, firm, painless bumps dotted her neck. By the time she turned 15, she could not walk nor talk and had difficulties learning. While under Bourneville’s care, her seizures intensified, firing in clusters, and over time, she lost feeling on the left side of her body. On the morning of May 7, 1879, she died in her hospital bed.

After examining her body post-mortem, Bourneville noticed many firm, opaque, “potato-like” protrusions on the surface folds of her brain. White, walnut-sized hard masses had also formed on both of her kidneys. He called the brain lesions “sclerose tubereuse des circonvolutions cerebrales,” or loosely translated, “tuberose sclerosis of brain convolutions.” This was one of the first observations of a unique, multi-system genetic disease called tuberous sclerosis or tuberous sclerosis complex (TSC).

After centuries of contributions from neurologists, pathologists, dermatologists, geneticists, and radiologists, it wasn’t until 1997 that American doctor David Kwiatkowski and colleagues at Brigham and Women’s Hospital in Boston discovered the gene TSC1 – or tuberous sclerosis 1 – and implicated it in the disease. Tuberous sclerosis complex is now believed to affect between one and two million people worldwide, and is implicated, albeit rarely, in some cancers.

Despite its reach, however, this genetic disease can be tricky to recognize. Most cases may be observed and diagnosed in infants before their first birthday, but because certain features of the disease can be subtle at first, years can pass before an official diagnosis.

Tuberous sclerosis complex (TSC), an illness named after a potato (tuber) and the atypical hardening of body tissues (sclerosis), affects various systems of the body.
Doctors generally recognize the disease by hallmark benign tumors, which can sprout in any organ, but most commonly reside in the brain, kidneys, eyes, lungs, heart, and skin. It also attacks the central nervous system, spawning an array of symptoms including seizures, delayed development, behavioral issues, skin irregularities, and kidney disease. Such were the symptoms observed in Bourneville’s teenage patient.

Tumor cells caused by tuberous sclerosis complex can sometimes spread to other parts of the body and become cancerous. When this happens, a patient is most likely to develop renal cell carcinoma (RCC), or less formally, kidney cancer. RCC occurs in about three percent of TSC patients, and usually before the age of 50.
These cancers start with a mutation, but in order to understand what happens when things go wrong, it’s first important to know what occurs when things go right.

A healthy TSC1 gene provides the instructions for cellular machinery to build a protein called hamartin. By itself, hamartin doesn’t do much. But once it finds and gloms onto its partner tuberin -a similarly-sized protein made by the gene TSC2 (tuberous sclerosis 2) – they embrace to form a complex that does a very important job: It suppresses cell growth. This glob of interlocking hamartin and tuberin proteins is called a tumor suppressor. It does just what its name suggests; it stops the growth of tumors by blocking other proteins from triggering cell growth and division.

When either the TSC1 or TSC2 genes are mutated -meaning there’s a change in the gene’s DNA sequence caused by mistakes in DNA replication or by damage from external factors such as UV light or cellular stress -the complex doesn’t function properly. And just as lifting a plug from a full bathtub causes a rush of water to descend through pipes, a malfunctioning tumor suppressor triggers a cascade of downstream effects.

One of those downstream effects is cell growth. A protein called MTOR, which stands for the mammalian target of rapamycin, switches on and causes cells to become enlarged and grow uncontrollably. This unchecked growth is what caused the brain and kidney protuberances in Boumeville’s patient. It is also implicated in cancer.

While cancer of the kidneys is the most common cancer seen in tuberous sclerosis complex patients, scientists have also observed a mutation in the TSC1 gene in some bladder cancers. In this instance, the mutation generally occurs in somatic cells, which are any cells in the body other than sperm or egg cells. Such a mutation causes the cell to produce little or no hamartin. When this happens in bladder cells, they begin to mature and divide without any regulating proteins (such as the hamartin/tuberin complex) to tell it to stop. Eventually if this uncontrolled cell growth invades nearby tissues and spreads throughout the body, it can become a cancerous tumor.

Paradoxically, however, TSC tumors generally don’t become cancerous. And scientists are trying to figure out why that is.

One of the biggest clues comes from the location of the initial mutation in the TSC1 gene. If the mistake begins in the TSC1or TSC2 gene in a parent’s sperm or egg cell and then gets passed on to their child who then develops tuberous sclerosis complex, he or she is likely to develop noncancerous tumors throughout the body. But if the mutation develops outside of the patient’s reproductive cells after a person is born, the resulting tumors are more likely to become cancerous.

While there is no cure for TSC and other issues relating to a mutation in the TSC1gene, there are many drugs that treat the symptoms of the disease.
One drug in particular, rapamycin (marketed as Rapamune), snuffs out cell proliferation by inhibiting the MTOR pathway discussed earlier. Because an overactive MTOR pathway is implicated in many cancers, and mutations in the TSCr and TSC2 genes tend to contribute to this hyperactivity, there is hope that this drug could be used to treat cancers due to mutations in these genes. However, the drug is still being tested in clinical trials and the Food and Drug Administration (FDA) has not yet approved it.

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