Tuberous Sclerosis: Genetics

Abstract Tuberous sclerosis is an autosomal‐dominant disorder characterised by seizures, intellectual disability, autistic spectrum disorder and the growth of benign tumours in multiple organs including the brain, skin, heart and kidneys. It is caused by mutations in either the TSC1 gene on 9q34 or the TSC2 gene on 16p13.3. The gene products, TSC1 and TSC2, interact and as a heterodimer act to integrate multiple of stimuli such as mitogenic stimulation, oxygen and energy levels into the control of diverse cell processes. One of the best characterised downstream targets of TSC1/TSC2 is mammalian target of rapamycin complex 1 (mTORC1), which regulates proteins synthesis, metabolism, autophagy and cell division amongst other cellular processes. Clinical trials in patients with tuberous sclerosis using mTOR inhibitors have shown promising results. Key Concepts: Tuberous sclerosis is an autosomal‐dominant multisystem disorder. Tuberous sclerosis is caused by mutations in either of two genes TSC1 or TSC2 . One of the key functions of the TSC1/TSC2 protein complex is to integrate signals from multiple stimuli to regulate cellular processes such as growth and division via the mammalian target of rapamycin (mTOR) pathway. Knowledge of the molecular pathology of tuberous sclerosis has been translated into clinical trials using mTOR inhibitors to treat manifestations of the condition.