KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further... Show moreKPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models.Kptn−/− mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants.Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1.By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity. Show less
Transport experiments in twisted bilayer graphene haverevealed multiple superconducting domes separated by cor-related insulating states 1–5 . These properties are generallyassociated with strongly... Show moreTransport experiments in twisted bilayer graphene haverevealed multiple superconducting domes separated by cor-related insulating states 1–5 . These properties are generallyassociated with strongly correlated states in a flat mini-bandof the hexagonal moiré superlattice as was predicted by bandstructure calculations 6–8 . Evidence for the existence of a flatband comes from local tunnelling spectroscopy 9–13 and elec-tronic compressibility measurements 14 , which report two ormore sharp peaks in the density of states that may be asso-ciated with closely spaced Van Hove singularities. However,direct momentum-resolved measurements have proved to bechallenging 15 . Here, we combine different imaging techniquesand angle-resolved photoemission with simultaneous real- andmomentum-space resolution (nano-ARPES) to directly mapthe band dispersion in twisted bilayer graphene devices nearcharge neutrality. Our experiments reveal large areas with ahomogeneous twist angle that support a flat band with a spec-tral weight that is highly localized in momentum space. The flatband is separated from the dispersive Dirac bands, which showmultiple moiré hybridization gaps. These data establish thesalient features of the twisted bilayer graphene band structure. Show less
