Glucokinase Gene Mutations: Structural and Genotype-Phenotype Analyses in MODY Children from South Italy

BACKGROUND: Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK). METHODOLOGY/PRINCIPAL FINDINGS: We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: approximately 59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT = 7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04). CONCLUSIONS: The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation

Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances

New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS