Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity.

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1), 2 (ITPR2), and 3 (ITPR3) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4+ lymphopenia, a quasi-absence of naïve CD4+ and CD8+ cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Benchmarking the performance of spin-component scaled CC2 in ground and electronically excited states.

A generalization of the spin-component scaling and scaled opposite-spin modifications of second-order Møller-Plesset perturbation theory to the approximate coupled-cluster singles-and-doubles model CC2 (termed SCS-CC2 and SOS-CC2) is discussed and a preliminary implementation of ground and excited state energies and analytic gradients is reported. The computational results for bond distances, harmonic frequencies, adiabatic and 0-0 excitation energies are compared with experimental results to benchmark their performance. It is found that both variants of the spin-scaling increase the robustness of CC2 against strong correlation effects and lead for this method even to somewhat larger improvements than those observed for second-order Møller-Plesset perturbation theory. The spin-component scaling also enhances systematically the accuracy of CC2 for 0-0 excitation energies for pi --> pi* and n --> pi* transitions, if geometries are determined at the same level.