SCN1B

Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma, the leading cause of irreversible blindness. We previously demonstrated that casein kinase-2 inhibition can promote retinal ganglion cell survival and axonal regeneration in rats after optic nerve injury. To investigate the underlying mechanism, in the current study we increased the intraocular pressure of adult rats to 75 mmHg for 2 hours and then administered a casein kinase-2 inhibitor (4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) by intravitreal injection. We found that intravitreal injection of 4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-¹H-benzimidazole promoted retinal ganglion cell survival and reduced the number of infiltrating macrophages. Transcriptomic analysis showed that the mitogen activated protein kinase signaling pathway was involved in the response to intraocular pressure elevation but was not modulated by the casein kinase-2 inhibitors. Furthermore, casein kinase-2 inhibition downregulated the expression of genes (Cck, Htrsa, Nef1, Htrlb, Prph, Chat, Slc18a3, Slc5a7, Scn1b, Crybb2, Tsga10ip, and Vstm21) involved in intraocular pressure elevation. Our data indicate that inhibition of casein kinase-2 can enhance retinal ganglion cell survival in rats after acute intraocular pressure elevation via macrophage inactivation.

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) β-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.

Atrial fibrillation (AFib) is characterized by a complex genetic component. We aimed to investigate the association between variations in genes related to cardiac ion handling and AFib in a cohort of Romanian patients with hypertrophic cardiomyopathy (HCM). Forty-five unrelated probands with HCM were genotyped by targeted next-generation sequencing (NGS) for 24 genes associated with cardiac ion homeostasis. Subsequently, the study cohort was divided into two groups based on the presence (AFib+) or absence (AFiB-) of AFib detected during ECG monitoring. We identified two polymorphisms (rs1805127 located in KCNE1 and rs55742440 located in SCN1B) linked to AFib susceptibility. In AFib+, rs1805127 was associated with increased indexed left atrial (LA) maximal volume (LAVmax) (58.42 ± 21 mL/m² vs. 32.54 ± 6.47 mL/m², p < 0.001) and impaired LA strain reservoir (LASr) (13.3 ± 7.5% vs. 24.4 ± 6.8%, p < 0.05) compared to those without respective variants. The rs55742440 allele was less frequent in patients with AFib+ (12 out of 25, 48%) compared to those without arrhythmia (15 out of 20, 75%, p = 0.05). Also, AFib+ rs55742440 carriers had significantly lower LAVmax compared to those who were genotype negative. Among patients with HCM and AFib+, the rs1805127 variant was accompanied by pronounced LA remodeling, whereas rs55742440's presence was related to a milder LA enlargement.