TSC2

Mutations in TSC2 cause tuberous sclerosis complex (TSC2-related TSC).
The clinical presentation is highly variable. Common features include seizures, cortical tubers, renal angiomyolipomas and cysts, pulmonary LAM (especially in females), skin lesions (e.g. hypomelanotic macules, angiofibromas), cardiac rhabdomyomas, and neurodevelopmental involvement (autism, intellectual disability).

Biological Function

The TSC2 gene encodes tuberin, part of the TSC1/TSC2 inhibitor complex that acts to regulate mammalian target of rapamycin (mTOR) signaling. Individuals with loss-of-function variants in TSC2 develop tuberous sclerosis, a genetic syndrome impacting multiple organ systems including the brain, lungs, skin, and kidneys. The exact symptom presentation varies in each individual.

Associated Conditions

Mutations in TSC2 cause TSC, a multi-system genetic disorder marked by benign tumor growth in the brain, kidneys, lungs, heart, and skin. The disorder has high variability in severity and symptoms, including seizures, developmental delay, autism, renal cysts or angiomyolipomas, and pulmonary lymphangioleiomyomatosis (LAM) in females.

Symptoms

TSC2-related TSC affects multiple organs, with variable severity:

Brain: Seizures, cortical tubers, subependymal nodules, autism, developmental delay
Skin: Hypopigmented macules, facial angiofibromas, shagreen patches
Kidneys: Angiomyolipomas, cysts, possible kidney dysfunction
Lungs (females): Lymphangioleiomyomatosis (LAM)
Heart: Rhabdomyomas, usually in infancy
Eyes/Bones: Retinal hamartomas, bone lesions (less common)

Research at Northwestern

Research at Northwestern is primarily aimed at resolving variants of uncertain significance (VUS) which confound achieving a precise genetic, and sometimes clinical, diagnosis of tuberous sclerosis. We, and our collaborators at the University of Washington, are working towards building a functional map of the tuberin protein which will act as a lookup table (LUT) to help clinical geneticists obtain a precise genetic diagnosis in many individuals.

Key publications include:

A deep mutational scan of TSC2 reveals protein functional domains and variant pathogenicity
Mathur A, Zhang X, Shah K, Suresh A, Gonzalez L, Boyle EA, Fields S, Jayaraman D, Bassik MC, Sweetser DA, O'Donnell-Luria AH, Berg MD, Millen KJ, Stamatoyannopoulos JA, Zoghbi HY, Gray LT.
bioRxiv. 2024 Jun 7.
Read more

Patient advocacy organizations

The TSC Alliance is a leading nonprofit organization dedicated to improving the lives of individuals affected by tuberous sclerosis complex (TSC). The Alliance supports scientific research, including ongoing work at Northwestern University, and partners with institutions worldwide to advance understanding, diagnosis, and treatment of TSC.

In addition to funding research, the TSC Alliance provides:

Patient and family support
Educational resources for clinicians and the public
Advocacy for improved access to care and policy change
Navigation services to help families manage TSC-related medical challenges