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Objective: To describe a new FHM kindred, and to analyse the functional consequences of the disease-associated ATP1A2 p.G301R mutation in human cellular models grown at 37°C.Patients and methods: Seven patients were clinically evaluated and gave informed consent for molecular analysis. Extra-pyramidal rigidity of the limbs was present in four subjects and in three of them tongue apraxia was also observed. ATP1A2 and CACNA1A were analysed by direct sequencing. Functional consequences of the mutation were investigated by cell viability assays, Western blots, and immunocytochemistry. Three-dimensional models of the human Na+/K+-ATPase α2 subunit were generated by homology modelling using SWISS-MODEL.Findings: Analysis of ATP1A2 showed a heterozygous mutation, c.901G>A predicting the replacement of arginine for glycine at residue 301 (p.G301R). Functional analysis suggested that the mutation completely abolished Na+/K+-ATPase function.Conclusions: The phenotypic spectrum of our FHM2 family includes some peculiar features. Functional data confirm that Na+/K+-ATPase haploinsufficiency caused by the ATP1A2 p.G301R mutation is responsible for FHM in the described family. [ABSTRACT FROM PUBLISHER]

This article describes how innovations are exploited in Campania (Italy) to improve health outcomes, quality of life, and sustainability of social and healthcare services. Campania's strategy for digitalization of health and care and for healthy aging is based on a person-centered, life-course, "One Health" approach, where demographic change is considered capable of stimulating a growth dynamic linked to the opportunities of combining the "Silver Economy" with local assets and the specific health needs of the population. The end-users (citizens, patients, and professionals) contribute to the co-creation of products and services, being involved in the identification of unmet needs and test-bed activity. The Campania Reference Site of the European Innovation Partnership on Active and Healthy Aging is a flexible regional ecosystem to address the challenge of an aging population with a life-course approach. The good practices, developed in the context of research and innovation projects and innovative procurements by local stakeholders and collaborations with international networks, have been allowing the transfer of innovative solutions, knowledge, and skills to the stakeholders of such a multi-sectoral ecosystem for health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Luca, Tramontano, Riccio, Trama, Buono, Losasso, Bracale, Annuzzi, Zampetti, Cacciatore, Vallefuoco, Lombardi, Marro, Melone, Ponsiglione, Chiusano, Bracale, Cafiero, Crudeli, Vecchione, Taglialatela, Tramontano, Iaccarino, Triassi, Roller-Wirnsberger, Bousquet and Illario.)

The muscarinic-regulated potassium current (M-current), formed by the heteromeric assembly of subunits encoded by the KCNQ2 and KCNQ3 genes, is a primary regulator of neuronal excitability; this regulation is accomplished by impeding repetitive firing and causing spike-frequency adaptation. Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal convulsions (BFNC), a rare autosomal-dominant generalized epilepsy of newborns, by reducing the maximal current carried by the M-channels without affecting ion selectivity or gating properties. Here we show that KCNQ2/KCNQ3 channels carrying a novel BFNC-causing mutation leading to an arginine to tryptophan substitution in the voltage-sensing S4 domain of KCNQ2 subunits (R214W) displayed slower opening and faster closing kinetics and a decreased voltage sensitivity with no concomitant changes in maximal current or plasma membrane expression. These results suggest that mutation-induced gating alterations of the M-current may cause epilepsy in neonates.