ESPE2023 Poster Category 1 Growth and Syndromes (75 abstracts)
Tuberous sclerosis complex 1 (TSC1) deficiency leads to increased proliferation of adipose progenitor cells – case report and in vitro studies
Antje Garten 1 , Julia Hentschel 2 , Sandy Richter 1 , Henriette Kiep 3 , Maria Arelin 3 , Konrad Platzer 2 , Andreas Merkenschlager 3 , Wieland Kiess 1 , Steffi Mayer 4 , Rami Abou Jamra 2 & Diana Le Duc 2
1Center for Pediatric Research, University Hospital for Children and Adolescents, Leipzig, Germany. 2Institute of Human Genetics, Leipzig, Germany. 3University Hospital for Children and Adolescents, Leipzig, Germany. 4University Hospital for Pediatric Surgery, Leipzig, Germany
Introduction&Aim: Activation of mechanistic target of rapamycin (mTOR) as a major regulator of adipogenesis and lipid accumulation is controlled by upstream regulators hamartin/tuberous sclerosis complex (TSC) 1 and tuberin/TSC2. Hamartin and tuberin form a protein complex that inhibits signal transduction to mTOR. The impact of TSC1 deficiency is not clearly defined in human adipose tissue. We identified a likely pathogenic TSC1 splicing variant in a lipoma of a 10year-old boy with developmental delay and potential tuberous sclerosis. We aim to assess the effect of this TSC1 variant on adipogenesis and proliferation of adipose precursors and we will establish a cell model to test potential therapeutic options.
Methods: To establish an in vitro model we used siRNA knockdown of TSC1 in SGBS and LipPD1 lipoma cells. We examined proliferation and adipocyte differentiation of TSC1 KD vs. control cells using Hoechst stain for cell nuclei and Nile Red as well as Oil Red O stain for lipid accumulation. Gene expression of adipogenesis markers was measured by qPCR, activation of mTOR and downstream effectors was assessed via Western blotting with phosphospecific antibodies.
Results: The boy presented with a large lipoma within the right gluteal muscle. To our knowledge, lipomas located elsewhere than in the renal region have not yet been described as part of the phenotypic spectrum of tuberous sclerosis. In the lipoma tissue we identified a loss of heterozygosity on chromosome 9 starting in the region 9q32 to 9q34.3 including TSC1. An mRNA analysis conducted in blood and lipoma showed that in lipoma tissue only the alternative, truncated transcript was expressed. Preliminary in vitro analyses in preadipocytes with TSC1 knockdown suggested a higher proliferation of TSC1 KD cells compared to control cells. There was no significant effect on lipid accumulation and expression of adipogenesis markers PPARγ, adiponectin and FASN. We detected an increased phosphorylation of ribosomal protein S6 in TSC1 KD cells, phosphorylation of other mTOR targets was not altered.
Conclusion: We conclude that the variant in TSC1 is probably causative for increased proliferation of preadipocytes leading to lipoma formation and a therapy with mTOR inhibitors may be beneficial.
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