Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Tuberous Sclerosis (TSC) [Q85.1]

OMIM numbers: 191100, 605284 (TSC1), 613254, 191092 (TSC2)

Dr. rer. nat. Karin Mayer

Scientific Background

Tuberous Sclerosis Complex (TSC, M. Bourneville Pringle) is an autosomal dominant multisystem disorder with high clinical variability. Incidence is approx. 1 in 7,000. Characteristics include multiple, local regions with incomplete and abnormal differentiation of the tissue, also known as hamartia, which are termed hamartomas if they show increased proliferation, however they remain benign. TSC may manifest in almost any organ; however brain, heart, kidneys, lungs, skin and eyes are most frequently affected. All organ manifestations are facultative; none of these signs and symptoms needs to be always detected. Some of the signs and symptoms are not of clinical significance; they indicate, however, that the person is predisposed. According to the current diagnostic criteria, published in 2013, the diagnosis TSC can be established both genetically and clinically. Therefore, the exclusive detection of a pathogenic mutation in the TSC1 or TSC2 gene is sufficient for the diagnosis. Clinical manifestations are categorized into 11 major criteria and 6 minor criteria. Both two major criteria or the combination of one major criterion and at least two minor criteria confirm TSC; one major criterion or at least two minor criteria give rise to suspicion of TSC.

Mutations in the TSC1 and TSC2 gene are the molecular cause of the disease. Mutations of the TSC1 and the TSC2 genes occur with the same frequency in families with several affected patients; 70% of all TSC cases, however, occur sporadically due to new mutations. In these cases, TSC1 is affected in only 10-15% of all patients; TSC2 in 70%. In total, TSC2 mutations are four times more frequent than TSC1 mutations. Both TSC genes are tumor suppressor genes, which act recessively on the cellular level, i.e. they only lead to the local formation of hamartomas if both homologous TSC genes are inactivated due to two independent mutations. The TSC1 and TSC2 gene products hamartin and tuberin form a complex and have a key function within fundamental signal transduction pathways which regulate cell adhesion, transcription and cell proliferation, vesicular transport and cell migration. The insulin-mediated mTOR signal transduction is the most significant one. The tuberin/hamartin complex inhibits the activity of serine kinase mTOR (mammalian Target of Rapamycin). Mutations in TSC1 or TSC2 cause overactivation of mTOR signal transduction and increased proliferation in the typical TSC lesions. Due to the interaction of hamartin and tuberin, the inactivation of both copies of one of the two TSC genes results in loss of function of the entire protein complex and therefore leads to the same pathogenesis. Excluding some exceptions, a clear genotype-phenotype correlation is not possible.

In case of a functional loss of the TSC1/TSC2 complex the activated mTOR signal transduction can be inhibited by medication. Clinical studies with TSC patients have shown that the mTOR inhibitors Rapamycin (Sirolimus, Rapamune®) and its derivative RAD001 (Everolimus, Afinitor®, Votubia®) inhibit the growth of angiomyolipomas of the kidney and of giant cell astrocytomas of the brain. Furthermore they may have a positive impact on angiofibromas in the face, epilepsy and the respiratory functions in lymphangiomyomatosis.

TSC1 consists of 23 protein coding exons; TSC2 of 41. So far, more than 1,800 mutations in both genes have been published. The mutations are distributed over almost all exons or adjacent intronic sequences and comprise all mutation types in both genes. The majority of all 470 mutations in the TSC1 gene that have been described lead to a prematurely shortened gene product; with a frequency of less than 17% and 3%, respectively, pathogenic missense mutations and larger deletions are relatively rare. Among the 1,350 mutations described in the TSC2 gene, all types of point mutations occur with more or less the same frequency. In contrast to the TSC1 gene, the deletions of larger gene areas are more frequent with approximately 6%; additionally, in 3/4 of these cases both the TSC2 gene and the adjacent PKD1 gene (responsible for autosomal dominant polycytic kidney disease (ADPKD)) is affected. Patients with this TSC2/PKD1 contiguous gene syndrome display clinical characteristics of both TSC and ADPKD with early onset of polycystic kidney disease. Mutation screening in both TSC genes by DNA sequencing detects approx. 90% of all known types of mutations. Up to 10% of all mutations in both TSC genes are larger deletions. In approximately 85% of all patients with clinically confirmed diagnosis of TSC, a mutation in one of the two TSC genes can be detected using a combination of the routine methods: Sanger sequencing and deletion/duplication screening by MLPA. In some of the cases which cannot be resolved using these methods, mutations in the regulatory regions of both TSC genes or genetic mosaics are present. They can be detected by deep sequencing of the entire genomic regions of both TSC genes.