RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias

Schematic representation of RGS3 isoforms, domains and encoded protein. Asterisks depict the position of the variant detected in family PSYAK2. Longer mRNA transcripts encode proteins that are predicted to localize to the cytosol or associate with the plasma membrane. Shorter, N-terminally truncated forms may be nuclear. Black boxes indicate noncoding exons. (A) RGS3 isoform NM_144488.8 encodes the protein with the highest molecular weight, consisting of 1198 amino acids. (B) RGS3 isoform NM_001282923.2 contains 22 exons with the variant c.649C > T within exon 4. (C) RGS3 isoform NM_17790.6 encodes a truncated protein. (D) RGS3 isoform NM_1276261.2 lacks exons encoding plasma membrane or cytoplasmic domains. (E) RGS3 isoform NM_1276260.2 encodes a protein that is N-terminally truncated. (F) RGS3 isoform NM_144490.4 is the shortest isoform. (G) Schematic representation of RGS3 isoform NP_652759.4 showing different domains. The c.649C > T, p.(Arg217Cys) variant is within the C2 domain, which is involved in Ca⁺²-dependent translocation of the RGS3 protein. (H) RGS3 inhibits the G-protein-mediated postreceptor signalling pathway. The C2 domain at the N-terminal translocates RGS3 from the cytosol to the plasma membrane, whereas the PDZ domain interacts with neuroligin and AMPAR GluR2, which further binds with EphrinB2. After translocation to the plasma membrane, the RGS domain of RGS3 interacts with the heterotrimeric G-proteins, which are composed of α, β and γ subunits. G-protein-coupled receptors activate guanylyl cyclase, which converts GMP to cGMP. It activates adenylyl cyclase to convert cAMP to AMP and activates multiple cytoplasmic proteins, including PED1C. The ligand binds with the ET-1 receptor and activates MAP kinase via cleavage of PIP2 to IP₃ (left side). IP₃ induces the uptake of Ca⁺² through protein kinase C. PED1C inhibits protein kinase C and reduces intracellular Ca⁺² by deterring the ET-1 signalling pathway. AMP = adenosine monophosphate; AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; cAMP = cyclic AMP; cGMP = cyclic GMP; ET-1 = endothelin-1; GAP = GTPase activating protein; GDP = guanosine diphosphate; GEF = guanidine exchange factor; GMP = guanosine monophosphate; GTP = guanosine triphosphate; IP₃ = inositol triphosphate; MAP = mitogen-activated protein; PDE1C = calmodulin dependent cyclic nucleotide phosphodiesterase; PIP2 = phosphatidylinositol 4,5-bisphosphate.

Schematic representation of IL1RAPL1 isoforms, domains and encoded protein. (A) IL1RAPL1 isoform NM_014271.4 has 11 exons encoding a 696 amino acid protein. An asterisk marks the position of the variant c.700A > G, p.(Thr234Ala), detected in family PSYAK3. (B) Schematic representation of multiple domains in IL1RAPL1, including the N-terminal signal peptide, 3 extracellular Ig-like domains, a TM region, a TIR domain and a C-terminal tail with a PDZ binding domain. (C) At the presynaptic terminal, Ig domains of PTP-δ interact with Ig domains of IL1RAPL1 and increase excitation across the synaptic cleft. The TIR domain interacts with RhoGAP2, with the help of NCS-1 calcium channels. RhoGAP2 is involved in GTPase intrinsic activity and regulates a number of neuronal signalling pathways. The PDZ binding motif of IL1RAPL1 interacts with the PDZ domain of PSD-95 by Ser-295 and regulates the synaptic localization of PSD-95. The C-terminal PDZ binding domain of IL1RAPL1 phosphorylates JNK by MEKK. JNK phosphorylation activates PSD-95 and induces maturation of the synapse. GTPase = guanosine triphosphatase; Ig = immunoglobulin; JNK = C-Jun terminal kinase; MAP = mitogen-activated protein; MEKK = MAP kinase kinase; NCS-1 = neuronal calcium sensor-1; PSD-95 = postsynaptic scaffolding protein-95; PTP-δ = protein tyrosine phosphatase δ; RhoGAP2 = Rho GTPase-activating protein 2; TIR = toll/interleukin-1R; TM = transmembrane.