An iPSC line (FINi003-A) from a male with late-onset developmental and epileptic encephalopathy caused by a heterozygous p.E1211K variant in the SCN2A gene encoding the voltage-gated sodium channel Nav1.2.

Many developmental and epileptic encephalopathies (DEEs) result from variants in cation channel genes. Using mRNA transfection, we generated and characterised an induced pluripotent stem cell (iPSC) line from the fibroblasts of a male late-onset DEE patient carrying a heterozygous missense variant (E1211K) in Nav1.2(SCN2A) protein. The iPSC line displays features characteristic of the human iPSCs, colony morphology and expression of pluripotency-associated marker genes, ability to produce derivatives of all three embryonic germ layers, and normal karyotype without SNP array-detectable abnormalities. We anticipate that this iPSC line will aid in the modelling and development of precision therapies for this debilitating condition.

The conformations of 13-vertex ML2C2B10 metallacarboranes: experimental and computational studies.

The docosahedral metallacarboranes 4,4-(PMe(2)Ph)2-4,1,6-closo-PtC(2)B(10)H(12), 4,4-(PMe(2)Ph)2-4,1,10-closo-PtC(2)B(10)H(12), and [N(PPh(3))2][4,4-cod-4,1,10-closo-RhC(2)B(10)H(12)] were prepared by reduction/metalation of either 1,2-closo-C(2)B(10)H(12) or 1,12-closo-C(2)B(10)H(12). All three species were fully characterized, with a particular point of interest of the latter being the conformation of the {ML2} fragment relative to the carborane ligand face. Comparison with conformations previously established for six other ML(2)C(2)B(10) species of varying heteroatom patterns (4,1,2-MC(2)B(10), 4,1,6-MC(2)B(10), 4,1,10-MC(2)B(10), and 4,1,12-MC(2)B(10)) reveals clear preferences. In all cases a qualitative understanding of these was afforded by simple MO arguments applied to the model heteroarene complexes [(PH3)2PtC(2)B(4)H(6)]2- and [(PH3)2PtCB(5)H(6)]3-. Moreover, DFT calculations on [(PH3)2PtC(2)B(4)H(6)]2- in its various isomeric forms approximately reproduced the observed conformations in the 4,1,2-, 4,1,6-, and 4,1,10-MC(2)B(10) species, although analogous calculations on [(PH3)2PtCB(5)H(6)]3- did not reproduce the conformation observed in the 4,1,12-MC(2)B(10) metallacarborane. DFT calculations on (PH3)2PtC(2)B(10)H(12) yielded good agreement with experimental conformations in all four isomeric cases. Apparent discrepancies between observed and computed Pt-C distances were probed by further refinement of the 4,1,2- model to 1,2-(CH2)3-4,4-(PMe3)2-4,1,2-closo-PtC(2)B(10)H(10). This still has a more distorted structure than measured experimentally for 1,2-(CH2)3-4,4-(PMe(2)Ph)2-4,1,2-closo-PtC(2)B(10)H(10), but the structural differences lie on a very shallow potential energy surface. For the model compound a henicosahedral transition state was located 8.3 kcal mol(-1) above the ground-state structure, consistent with the fluxionality of 1,2-(CH2)3-4,4-(PMe(2)Ph)2-4,1,2-closo-PtC(2)B(10)H(10) in solution.

The synthesis and characterisation of 4,1,2-MC2B10 metallacarboranes.

Reduction of the tethered carborane 1,2-(CH2)3-1,2-closo-C2B10H10 followed by treatment with CoCl2/NaCp, [(p-cymene)RuCl2]2(p-cymene=C6H4MeiPr-1,4), (PMe2Ph)2PtCl2 or (dppe)NiCl2(dppe=Ph2PCH2CH2PPh2) affords reasonable yields of the new 13-vertex metallacarboranes 1,2-(CH2)3-4-Cp-4,1,2-closo-CoC2B10H10 (1), 1,2-(CH2)3-4-(p-cymene)-4,1,2-closo-RuC2B10H10 (2), 1,2-(CH2)3-4,4-(PMe2Ph)2-4,1,2-closo-PtC2B10H10 (3) and 1,2-(CH2)3-4,4-(dppe)-4,1,2-closo-NiC2B10H10 (4), respectively. All compounds were characterised spectroscopically and crystallographically. The cobalt and ruthenium species 1 and 2 have Cs symmetry in both solution and the solid state, having henicosahedral cage structures featuring a trapezoidal C1C2B9B5 face. The platinum and nickel compounds 3 and 4 have asymmetric docosahedral cage structures in the crystal (the more so for 4 than for 3) although both appear, by 11B and 31P NMR spectroscopy, to have Cs symmetry in solution. Low-temperature experiments on the more soluble platinacarborane could not freeze out the diamond-trapezium-diamond fluctional process that we assume is operating in solution, and we therefore conclude that this process has a relatively low activation barrier, probably <35 kJ mol-1.