TSC1 – Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder marked by benign hamartomas in the brain, heart, skin, and kidneys. Pathogenic variants in TSC1 (hamartin) or TSC2 (tuberin) disrupt inhibition of mechanistic target of rapamycin complex 1 (mTORC1), leading to dysregulated cell growth and proliferation. TSC1 encodes a 1,164-amino-acid protein that forms a functional complex with TSC2, integrating signals from PI3K-Akt and Rheb to restrain mTORC1 activity and downstream effectors such as S6 kinase 1 (S6K1).

Clinical Validity

The association between TSC1 and TSC (MONDO:0001734) is classified as Strong based on identification of TSC1 truncating variants in at least 31 unrelated probands (PMID:10205261), including both sporadic and familial cases, with independent reports of de novo events and segregation of pathogenic alleles in multiplex kindreds (PMID:25900779). Functional concordance is demonstrated by faithful replication of TSC phenotypes in Tsc1 knockout mice (PMID:11438694).

Genetic Evidence

TSC1 mutations show an autosomal dominant inheritance pattern with high penetrance. Segregation has been documented in pedigrees with multiple affected relatives (n=4) sharing the same truncating allele (PMID:25900779). Over 150 distinct TSC1 variants—predominantly frameshift and nonsense lesions—have been reported across >30 unrelated probands (PMID:10205261). A recurrent de novo duplication in exon 15, c.1680_1702dup (p.Gly568fs), was identified in an infant presenting with cardiac rhabdomyomas and subependymal nodules (PMID:10340649). This exemplifies the loss-of-function spectrum that underlies TSC1‐mediated disease.

Experimental / Functional Evidence

Mechanistically, hamartin deficiency results in unchecked mTORC1 signaling. TSC1-TSC2 complex disruption leads to hyperphosphorylation of S6K1 at Thr-229 and Thr-389, activating protein synthesis and cell growth (PMID:14993219). Tsc1 knockout mice develop renal and hepatic hamartomas and exhibit embryonic lethality, underscoring haploinsufficiency as a disease mechanism (PMID:11438694).

Conflicting Evidence

No robust studies have refuted the TSC1–TSC association. Cases lacking detectable TSC1/TSC2 mutations often display milder phenotypes and may represent mosaicism or alternative loci.

Integration & Clinical Utility

Genetic screening for TSC1 truncating variants, notably c.1680_1702dup (p.Gly568fs), is critical for confirming a TSC diagnosis, guiding surveillance for neurological and cardiac manifestations, and informing mTORC1‐targeted therapies. The combination of strong genetic and functional data supports TSC1 testing in patients with suggestive features even in the absence of overt multiorgan involvement.

Key Take-home: TSC1 haploinsufficiency due to truncating variants causes dysregulated mTORC1 activity and classic tuberous sclerosis complex, actionable by genetic diagnosis and mTOR inhibitors.

References

• Novel 23-base-pair duplication mutation in TSC1 exon 15 in an infant presenting with cardiac rhabdomyomas. American journal of medical genetics • 1999 PMID:10340649
• Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. American journal of human genetics • 1999 PMID:10205261
• A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proceedings of the National Academy of Sciences • 2001 PMID:11438694
• Critical role of T-loop and H-motif phosphorylation in the regulation of S6 kinase 1 by the tuberous sclerosis complex. The Journal of biological chemistry • 2004 PMID:14993219

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