Mutations in IRS4 are associated with central hypothyroidism

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutatio

Molecular mechanisms involved in pulmonary arterial hypertension development

Pulmonary arterial hypertension (PAH) is an elevation in pulmonary arterial pressure, characterized by symptoms of dyspnea, chest pain, decrease in exercise tolerance-fatigue, syncope and, if untreated, PAH leads to right heart failure. In PAH, there is an imbalance between mediators of vasodilation and vasoconstriction (e.g. nitric oxide and prostacycline – potent vasodilators, platelet inhibitor and antimitogens are decreased in PAH, while thromboxane, vasoconstrictor and platelet activator is increased in PAH, resulting in smooth muscle hypertrophy of small vessels, adventitial and intimal proliferation, and plexiform vascular lesions with vascular thrombosis). Standard diagnostic procedures for PAH include physical examination, pulmonary function testing, radiographic imaging, transthoracic echocardiography, right heart catheterization. Current drugs include synthet c prostanoids (iloprost, epoprostenil, beraprost, treprostinil) – vasodilators and antiplatelet agents. Phosphodiesterase-5 inhibitors decrease the breakdown of cGMP, increasing its intracellular levels, leukotriene receptor antagonist, – zafirlukast, decreases pulmonary arterial and venous pressure. Endothelin receptor blockers, bosentan, decrease pulmonary vascular resistance and improve results of functional tests. Other treatments are: anticoagulants, calcium-channel blockers, positive airway pressure therapy for obstructive sleep apnea, or oxygen for hypoxemia, and surgery. In conclusion, although there are some promising drugs in therapy of PAH, there is a need to develop new ones, together with surgical approaches, in order to increase the survival of patients with PAH. Gene and cell therapy could be expected as future perspectives