Crosstalk of Hedgehog and mTORC1 Pathways

Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved

Generation of induced pluripotent stem cells, KCi004-A derived from a male with Parkinsońs disease and homozygous for the PINK1 variant c.1366C > T, p.Gln456*

Disease causing variants in PINK1 lead to Parkinsońs disease (PD) with early age of onset and slow disease progression. Loss of mitochondrial function is a signal of bioenergetic stress, PINK1 accumulates on the outer mitochondrial membrane and initiates ubiquitination and degradation of damaged mitochondria by mitophagy. Here we describe the successful generation of an induced pluripotent stem cell line (iPSC) KCi004-A from a PD patient homozygous for the disease- causing variant c.1366C > T, p.Gln456* in PINK1. For the generation we transfect a fibroblast culture from the patient with a non-integrative self-replicating RNA vector

Generation of induced pluripotent stem cells, KCi001-A derived from a Bardet-Biedl syndrome patient compound heterozygous for the BBS1 variants c.1169T>G/c.1135G>C

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with a wide range of symptoms including obesity, retinal dystrophy, polycystic kidney disease, polydactyly, hypogonadism and learning difficulties. Here we describe the successful generation of an induced pluripotent stem cell (iPSC) KCi001-A from a BBS patient compound heterozygous for two disease causing BBS1 variants c.1169T>G, p. (Met390Arg)/c.1135G>C, p.(Gly370Arg).Resource tableUnlabelled TableUnique stem cell line identifierKCi001-AAlternative name(s) of stem cell lineBBS1 Clone10InstitutionKennedy Center, RigshospitaletContact information of distributorLisbeth Birk Møller, [email protected] of cell lineInduced pluripotent stem cell line (iPSC)OriginHumanAdditional origin infoFemale, CaucasianCell sourceDermal fibroblastsClonalityClonalMethod of reprogrammingNucleofection with non-integrating episomal plasmids carrying OCT3/4, SOX2, KLF4, L-MYC, LIN28 and shP53Genetic modificationNAType of modificationNAAssociated diseaseAutosomal recessive Bardet-Biedl syndromeGene/locusBBS1, Chr11: g.66293652 T > G, p.(Met390Arg); g.66293618G > C, p.(Gly379Arg); compound heterozygous.Ref sequence: NM_024649.4Method of modificationNAName of transgene or resistanceNAInducible/constitutive systemNADate archived/stock date25-01-2018Cell line repository/bankNAEthical approvalThe study was approved by the regional scientific ethical committee in the Capital Region of Denmark (H-3-2014-140). Written informed consent was obtained from the patients

Generation of induced pluripotent stem cells, KCi002-A derived from a patient with Bardet-Biedl syndrome homozygous for the BBS10 variant c.271insT

Bardet-Biedl syndrome (BBS) is genetically heterogeneous with at least 21 genes involved, and BBS10 encodes, together with BBS6 and BBS12, chaperonin-like proteins which are important for the assembly of the multiprotein complex, the BBSome encoded by other BBS genes. Here we describe the successful generation of an induced pluripotent stem cell (iPSC) line KCi002-A from a male with BBS, homozygous for the disease causing variant c.271insT, p.(Cys91fsX95) in BBS10.Resource tableUnlabelled TableUnique stem cell line identifierKCi002-AAlternative name(s) of stem cell lineBBS10 Clone1AInstitutionRigshospitalet, Kennedy CenterContact information of distributorLisbeth Birk Møller, [email protected] of cell lineinduced pluripotent stem cell (iPSC)OriginHumanAdditional origin infoMale, CaucasianCell sourceDermal fibroblastsClonalityClonalMethod of reprogrammingNucleofection with non-integrating episomal plasmids carrying OCT3/4, SOX2, KLF4, L-MYC, LIN28 and shP53Genetic modificationNAType of modificationNAAssociated diseaseAutosomal recessive Bardet-Biedl syndromeGene/locusBBS10, Chr 12: g.7674149insT, p.(Cys91fsX95), homozygous.Ref sequence: NM_024685.3Method of modificationNAName of transgene or resistanceNAInducible/constitutive systemNADate archived/stock date25-01-2018Cell line repository/bankNAEthical approvalThe study was approved by the regional scientific ethical committee in the Capital Region of Denmark (H-3-2014-140). Written informed consent was obtained from the patients

Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in the skin and other organs, including brain, heart, lung, kidney and bones. TSC is caused by mutations in TSC1 and TSC2. Here, we present the TSC1 and TSC2 variants identified in 168 Danish individuals out of a cohort of 327 individu