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Second Gene Responsible for Tuberous Sclerosis Complex Identified; TSC1 Finding on Chromosome 9 Follows 1993 Discovery of TSC2 Gene

For release: Thursday, August 7, 1997

Scientists have identified the second of two genes that cause tuberous sclerosis complex (TSC), a relatively common developmental disorder characterized by a number of abnormalities, including seizures, benign tumors in several organs, and variable emotional and cognitive disabilities. The discovery, to be reported in the August 8, 1997, issue of Science* by David Kwiatkowski, M.D., Ph.D., and colleagues at Brigham and Women's Hospital in Boston, was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI), both components of the National Institutes of Health.

Investigators located the TSC1 gene on chromosome 9. The gene makes a protein called hamartin, named after hamartomas, a type of tumor common to TSC and comprised of multiple cell types. Affected individuals have a mutation in either the TSC1 gene or the TSC2 gene. The TSC2 gene, which codes for a protein called tuberin, is located on chromosome 16 and was identified in 1993 by a European consortium of investigators. Both the TSC1 and TSC2 genes are thought to function as tumor suppressor genes and join more than a dozen other such genes that play an important role in the control of cell growth. In their normal form, tumor suppressor genes keep cells from multiplying unchecked in the body and prevent tumor development.

TSC occurs in one in 6,000 live births and affects a total of 40,000 Americans and 1,000,000 people worldwide. It is called a complex because of the wide range of clinical manifestations. Clinical signs may be subtle and, as a result, TSC can go unrecognized or misdiagnosed for many years. Although in some individuals it may take considerable time before symptoms develop, TSC is known primarily as a childhood disorder. Generally speaking, the clinical manifestations of TSC are the same for both genes. Seizures are the most common symptom. Other common features include tumors of the brain, kidneys, eyes, and other organs and a salmon-colored, seed-like rash on the face. These facial bumps are actually small benign tumors that have a vascular, dermal, and connective tissue component to them. Individuals with TSC may also experience diminished intellectual function, autism, sleep disturbances, or hyperactivity.

"Tuberous sclerosis complex presents us with the full spectrum of neurodevelopmental problems, all within the context of a single disorder, and each one representing a challenge to physicians," said Giovanna Spinella, M.D., a pediatric neurologist from NINDS. "This finding gives us an opportunity to learn about how a single gene product results in such a devastating and often disabling array of problems, whether they are seizures, autism, or tumors in multiple organs."

Brain scans may reveal an array of abnormalities, especially cortical tubers, which are firm, potato-like nodules that give the disorder its name and are made up partly of abnormal neuronal cells and glial cells, the brain's connective tissue. Other brain abnormalities include distortion and migration of certain neurons.

TSC is inherited as an autosomal dominant disorder, meaning that any person with TSC has a 50 percent chance of transmitting the defective gene to each of his or her children, who will then have TSC. Like another neurogenetic disorder called neurofibromatosis, TSC has a high rate of sporadic mutation, meaning the disease can affect any family -- regardless of genetic history. Sporadic mutations are believed to occur around the time of fertilization and account for more than 50 percent of TSC cases.

"Much of the motivation for our research comes from the fact that around one-half of children with tuberous sclerosis are moderately to severely affected, and this creates lifelong worry for parents and physicians alike," said Dr. Kwiatkowski, of Harvard Medical School and the paper's lead author. "We plan to now turn our efforts toward comprehensive analysis of the mutations that occur in TSC1 and TSC2, understanding the function of the proteins these genes encode, and, particularly, development of animal models of both TSC1 and TSC2 disease. The idea is to then use the animal models to understand how the disease occurs and explore potential therapies." The gene identification project was a collaborative research effort carried out by scientists in Boston at Brigham and Women's Hospital and MIT, and in the UK and the Netherlands.

In the study, mutations in the TSC1 gene were identified in 42 TSC patients or families and in about half the mutation consisted of a deletion of 1 to 4 base pairs of DNA. The other patients had any one of a variety of abnormalities, including single base insertions, a larger deletion of 10 to 30 base pairs of DNA, or single base mutations. The type of mutation seen in the TSC1 gene resembles those seen in another tumor suppressor gene called p53 which has been linked to apoptosis, or programmed cell death, and has been called the "guardian of the genome."

"This finding has tremendous meaning for the future health and quality of life of so many individuals," said Vicky Holets Whittemore, Ph.D., Vice President for Medical and Scientific Affairs at the National Tuberous Sclerosis Association, which also supported the work. "We can now move toward diagnostic testing, as well as therapies for TSC. At the same time, we are optimistic that an understanding of how TSC develops will be important in improving our understanding of autism and seizure disorders not related to TSC."

The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain. NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.

*The TSC1 Consortium. "Identification of the Tuberous Sclerosis gene (TSC1) on chromosome 9q34," Science, Volume 277, August 8, 1997 (pp. 805-808).

Originally prepared by Stephanie Clipper, NINDS Office of Communications and Public Liaison.

Last Modified August 7, 2009