What is the cell of origin in tuberous sclerosis?

Cell of Origin in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) originates from cells that have undergone a "second-hit" mutation in either the TSC1 or TSC2 genes, following an inherited or de novo germline mutation, leading to dysregulation of the mTOR signaling pathway and subsequent hamartoma formation in multiple organs. 1, 2

Genetic Basis of TSC

Primary Mutations

• TSC is caused by inactivating pathogenic variants in either:

  • TSC1 gene (chromosome 9q34) - encoding the protein hamartin
  • TSC2 gene (chromosome 16p13.3) - encoding the protein tuberin 1

• Distribution of mutations:

  • TSC2 mutations are more common than TSC1 mutations (approximately 80% vs 20% of cases) 3
  • Most pathogenic variants (>90%) arise from small genetic alterations 1
  • Large genomic events occur in approximately 4.7% of TSC2 and 0.7% of TSC1 cases 1

Two-Hit Hypothesis and Cell of Origin

The development of hamartomas in TSC follows the "two-hit" tumor suppressor model:

1. First hit: Germline mutation in either TSC1 or TSC2 (present in all cells)
2. Second hit: Somatic loss or intragenic mutation of the corresponding wild-type allele in specific cells 3

• The cells that undergo this second hit become the cells of origin for TSC-related lesions
• These cells lose normal TSC1-TSC2 protein complex function, leading to:
  • Dysregulation of the mTOR signaling pathway
  • Uncontrolled cell growth
  • Formation of hamartomas in multiple organs 2, 4

Cell-Specific Manifestations

Different cell types affected by the second hit lead to various TSC manifestations:

1. Neural cells: Cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas 4

2. Smooth muscle-like cells:

   • Alpha-actin-positive smooth muscle-like cells with loss of heterozygosity for the TSC2 gene have been isolated from renal angiomyolipomas 5
   • These cells show abnormal growth characteristics, requiring epidermal growth factor (EGF) and constitutively exhibiting high S6K phosphorylation 5

3. Renal cells: Various renal manifestations, including:

   • Angiomyolipomas
   • Renal cysts
   • Eosinophilic vacuolated tumors (rare in TSC patients) 1
   • Renal cell carcinoma (occurs in 3-5% of TSC patients) 2

Clinical Implications of Cell of Origin

The specific cell type affected and the nature of the mutation influence disease severity:

• TSC2 vs TSC1 mutations:

  • TSC2 mutations generally cause more severe disease 3
  • Intellectual disability is significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases 3
  • Different gene expression responses are triggered by TSC1 vs TSC2 mutations 6

• Mosaicism:

  • Approximately 10-15% of patients with clinical TSC have no identifiable mutations in standard testing 1, 2
  • Most of these patients have mosaicism for TSC2 or, less commonly, TSC1 mutations 1
  • Mosaic allele frequency varies across tissues, reflecting the heterogeneous distribution of affected cells 1

Clinical Pearls and Pitfalls

• Diagnostic pitfall: Standard genetic testing may miss mosaic mutations, especially if the mosaic allele frequency is low (<2%) 1

  • High-sensitivity genetic analysis is recommended to detect pathogenic alleles with frequencies as low as 1% 1

• Management pitfall: The multisystem nature of TSC requires coordinated care by specialists to effectively manage the complex manifestations 2

  • Inadequate surveillance can lead to delayed diagnosis and treatment of TSC-related complications 2

• Genetic counseling pitfall: The risk of TSC in subsequent pregnancies for parents of a child with sporadic TSC is approximately 1-2% due to possible germ cell mosaicism 1

The understanding of the cell of origin in TSC has important implications for targeted therapies that address the dysregulated mTOR pathway resulting from the loss of normal TSC1-TSC2 complex function.