Familial Risk and Resilience Moderate the Association Between Intolerance of Uncertainty and Youth Suicidal Ideation.

Short QT Syndrome (SQTS) is a rare, but highly lethal, inheritable channelopathy characterized by an abnormally short QT interval on the electrocardiogram (ECG) and an increased risk for atrial and life-threatening ventricular arrhythmia. SQTS is frequently associated with sudden cardiac death (SCD), which is often the first manifestation of the disease with devastating consequences to the patient and their family. Approximately 250 cases have been diagnosed in nearly 150 families worldwide, all during the last two decades. Despite their heterogeneous phenotype, the penetrance of the SQTS causative mutations is remarkable, and patients experience a poor quality of life. Therefore, there is an urgent need to improve the diagnosis and prevent SCD of SQTS patients. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances, and related disorders associated with SQTS remain incompletely understood. SQTS-linked variants in (SQTS1), (SQTS2), (SQTS3), and (SQTS8) are the only validated genotype-positive SQTS subtypes to date. The SQTS1-causative mutations hERG and hERG are the most common (25.9% of genotyped probands) and second most common (18.5%), respectively, of the clinically occurring SQTS variants. Focusing on SQTS3, the Kir2.1 mutation was originally described in an 8-year-old girl with a QTc interval of 194 ms, paroxysmal atrial fibrillation (AF) and ventricular fibrillation (VF) inducibility. The patient also presented multiple other disorders, such as severe mental retardation, abnormal proliferation of esophageal blood vessels, epilepsy, and Kawasaki disease. She suddenly died ten years after diagnosis. The methionine 301 in Kir2.1 forms a pore-facing loop region, and functional analysis in heterologous expression systems revealed that its replacement with a lysine abolished I in homozygosis and increased outward I in heterozygosis. SQTS3 is caused by mutations in the gene that encodes Kir2.1, a strong inward-rectifier potassium channel. Kir2.1 is responsible for I, which is essential in maintaining the resting membrane potential (RMP) and the final phase of action potential (AP) repolarization. Kir2.1 conductance changes (rectifies), and the slope of its current/voltage (IV) relationship is modified at voltages positive to the K equilibrium potential, being the current abolished at voltages close to 0 mV. Inward rectification of Kir2.x channels results from blockade by intracellular magnesium and polyamines (spermine, spermidine and putrescine), which upon membrane depolarization penetrate the cytoplasmic pore of the channel, binding to specific negatively charged residues and obstructing the outward flow of potassium. Spermine is the main channel blocker responsible for inward rectification, followed by spermidine, putrescine, and magnesium. Kir2.1 channels possess multiple polyamine binding sites. They are negatively charged regions, one in the transmembrane domain, involving D172, and the other in the cytoplasmic region, involving E224, D255, D259 and E299. The initial step in the rectification process involves the interaction of polyamines with E224 and E299 located in the COOH-terminus of the Kir2.1 channel. The second step is more voltage-dependent and implies the binding of polyamines at the D172 residue, which is deeper inside the Kir2.1 pore. Mutations at any of the above residues result in a defective inward rectification of I. Polyamines are non-toxic and have been shown to be important in aging, cancer and other diseases, but inward rectification at depolarized potentials is likely their most important function. However, to our knowledge, polyamines have never been considered as a therapeutic option in SQTS3.