TSC2 – Lymphangioleiomyomatosis

Tuberous sclerosis complex gene TSC2 encodes tuberin, a key negative regulator of the mTOR pathway. Loss-of-function mutations in TSC2 underlie pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease characterized by proliferation of abnormal smooth muscle–like cells in women of reproductive age. Both sporadic and TSC-associated forms of LAM converge on biallelic TSC2 inactivation, implicating haploinsufficiency plus second-hit mechanisms in pathogenesis.

In sporadic LAM, somatic TSC2 mutations were identified in 5 of 7 angiomyolipoma lesions and mirrored in pulmonary LAM cells, while absent from normal tissues, demonstrating lesion-specific loss of tuberin (PMID:10823953). In a cohort of 14 women with TSC-associated LAM, germline TSC2 variants were detected in 7 individuals, compared with a single TSC1 case, confirming predominant TSC2 involvement in TSC-LAM (PMID:11208653).

A retrospective Chinese multicenter study of 61 LAM patients detected TSC1/2 variants in 46 subjects (75.4%), with TSC2 variants comprising 88.4% of total, including SNVs, indels, large duplications, and copy-neutral LOH events (PMID:31856217). Recurrent missense and truncating mutations cluster in the GAP-related domain and C-terminal regions, supporting critical structure–function regions.

Mechanistically, TSC2-deficient LAM/TSC cells exhibit EGF-dependent proliferation, focal adhesion kinase–Akt–mTOR pathway inactivation, anchorage-independent survival, and stem-cell–like quiescence; these phenotypes are reversed by anti-EGFR antibodies and rapamycin treatment (PMID:24606538). In vitro and in vivo studies show that AGTR1 inhibition induces cytocidal Klotho-mediated death specifically in TSC2-null cells and attenuates tumor progression, reinforcing therapeutic targeting of mTOR and RAS pathways (PMID:36220392). Rheb GTPase is directly regulated by TSC2 GAP activity, linking tuberin loss to unchecked mTOR signaling (PMID:12771962).

To date, over 60 unrelated LAM probands harbor TSC2 variants, with somatic second hits consistently demonstrated in lesions. There is limited family segregation data due to the sporadic nature of most cases. The weight of genetic and experimental concordance supports a Strong ClinGen gene–disease association for TSC2 in LAM. Genetic evidence is Strong based on numerous unrelated probands with germline and somatic TSC2 alterations reaching the genetic case-level cap. Functional evidence is Moderate given robust in vitro and in vivo models recapitulating human disease.

Key Take-home: TSC2 mutation screening and mTOR/RAS-targeted therapies provide actionable strategies for diagnosis and management of lymphangioleiomyomatosis.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2000 • Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. PMID:10823953
• American Journal of Respiratory and Critical Care Medicine • 2001 • The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. PMID:11208653
• PLoS One • 2019 • Mutation spectrums of TSC1 and TSC2 in Chinese women with lymphangioleiomyomatosis (LAM). PMID:31856217
• Journal of Cellular and Molecular Medicine • 2014 • TSC2 epigenetic defect in primary LAM cells. Evidence of an anchorage-independent survival. PMID:24606538
• The Journal of Biological Chemistry • 2022 • Angiotensin II receptor type 1 blockade regulates Klotho expression to induce TSC2-deficient cell death. PMID:36220392
• Nature Cell Biology • 2003 • Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. PMID:12771962

Evidence Based Scoring (AI generated)