The emerging role of the inwardly rectifying K+ channels in autism spectrum disorders and epilepsy

Autism is a complex behavioral disorder that develops prior to age three years and is distinguished by high heritability. Many genes predisposing to autism spectrum disorders (ASDs) have been identified. These findings have demonstrated that ASDs are etiologically heterogeneous; although, the mutations underlying ASDs are identifiable only in a minority of patients. Indeed, the causes of ASDs are unknown in more than 70% of patients. Recently, we have described two unrelated families whose affected individuals display a characteristic triad of symptoms of autism; such as impairments in social interaction, impairments in communication, restricted interests and repetitive behavior. They also displayed other symptoms commonly observed in autistic individuals; such as gait imbalance, clumsiness, mental retardation and epilepsy. The genetic analysis of these families resulted in the identification of new heterozygous point mutations in the KCNJ10 gene that encodes the inwardly-rectifying K+ channel Kir4.1 expressed predominantly, but not exclusively, in astrocytes. Functionally, the mutated channels exhibited a phenotype consistent with gain-of-function defects. These new findings highlight the emerging role of inwardly-rectifying K+ channels and astrocyte dysfunction in autism spectrum disorders associated with epilepsy.peer-reviewe

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En este artículo las autoras describen investigaciones que han demostrado que el comportamiento pro-social y la empatía pueden contribuir al bienestar psicofísico, disminuyendo niveles de estrés crónico y mejorando la respuesta inmune. Basadas en esta evidencia y con el fin de promover estas capacidades en niñas y niños, desarrollaron un programa que consiste en realizar, en el ambiente diario de los chicos, junto a sus maestras, actividades lúdicas grupales que favorecen la auto-percepción, la colaboración empática y la toma de perspectiva. Observamos que, al participar de estas experiencias, las niñas y niños amplían sus lazos sociales, aumentando la inclusión y disminuyendo el rechazo entre pares. Encontraron además un aumento en las actitudes solidarias y una reducción del estrés crónico. Estos resultados muestran como la colaboración empática puede aprenderse y desarrollarse en la escuela, beneficiando así la salud y las relaciones sociales

Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders

CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them

Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel

The KCNA1 gene encodes the subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation

A review of “Children and adults at home all day long: A world to share and recreate”. An interdisciplinary tool addressed to childhood, families and educators in the context of pandemic and isolation

Se reseña una iniciativa interdisciplinaria de comunicación pública de la ciencia dirigida a niños/as, familiares y educadores que busca atender diversas problemáticas asociadas a la convivencia prolongada en hogares en contexto de aislamiento y distanciamiento social debido a la pandemia de COVID-19. Articula conocimientos científicos relevantes para la situación actual con los conocimientos y prácticas que se implementan y recrean en los hogares. El proyecto se plasma en más de 30 micros comunicativos multimodales y multimediales creados por las científicas del equipo, ilustrados por artistas y publicados en redes sociales y otros medios masivos de comunicación. Tanto los enfoques epistemológicos, pedagógicos y comunicativos articulados en esta propuesta como los micros comunicativos constituyen herramientas disponibles para educadores en Biología.We offer a review of “Children and adults at home all day long: a world to share and recreate”, an interdisciplinary initiative of public communication of science that seeks to approach problems associated with a prolonged coexistence at home in the context of social isolation or social distancing in Argentina, due to the COVID-19 pandemic. This initiative is addressed to children, their families, and educators. It articulates scientific knowledge considered timely with knowledge and practices that already exist at home. A set of more than 30 multimodal brief pieces has been created by the scientists in the team, illustrated by artists and published in social media and mass media. The epistemological, pedagogical and communicational approaches the present project stands on, as well as the set of materials produced are tools available for Biology educators.publishedVersionFil: Bengtsson, Astrid. Universidad Nacional de Río Negro, Argentina.Fil: Bengtsson, Astrid. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina.Fil: Bugallo, Lucía. Universidad Nacional del Comahue; Argentina.Fil: Bugallo, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Patagónico de Estudios de Humanidades y Ciencias Sociales; Argentina.Fil: Coccoz, Verónica. Río Negro, ArgentinaFil: D’Adamo, Paola. Universidad Nacional del Comahue; Argentina.Fil: D’Adamo, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Patagónico de Estudios de Humanidades y Ciencias Sociales; Argentina.Fil: Lozada, Mariana. Universidad Nacional del Comahue; Argentina.Fil: Lozada, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Biodiversidad y Medioambiente; Argentina.Fil: Méndez, Laura Marcela. Universidad Nacional del Comahue; Argentina.Fil: Méndez, Laura Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Patagónico de Estudios de Humanidades y Ciencias Sociales; Argentina.Fil: Pedrazzini, Ana. Universidad Nacional del Comahue; Argentina.Fil: Pedrazzini, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Patagónico de Estudios de Humanidades y Ciencias Sociales; Argentina.Fil: Pérez, Soledad. Universidad Nacional de Río Negro, Argentina.Fil: Pérez, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Diversidad Cultural y Procesos del Cambio; Argentina.Fil: Rapela, Verónica. Ciudad autónoma de Buenos Aires; Argentina.Fil: Salsa, Analía. Universidad Nacional de Rosario; Argentina.Fil: Salsa, Analía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Rosario de Investigaciones en Ciencias de la Educación; Argentina.Fil: Tozzini, Alma. Universidad Nacional de Río Negro, Argentina.Fil: Tozzini, Alma. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Diversidad Cultural y Procesos del Cambio; Argentina.Fil: Scheuer, Nora. Universidad Nacional del Comahue; Argentina.Fil: Scheuer, Nora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Patagónico de Estudios de Humanidades y Ciencias Sociales; Argentina.Fil: Ventura, Ana Clara. Universidad Nacional del Comahue; Argentina.Fil: Ventura, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Patagónico de Estudios de Humanidades y Ciencias Sociales; Argentina

A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.TelethonAssociazione Serena Talarico per i giovani nel mondo and Fondazione Giuseppe Tomasello O.N.L.U.S.Mitocon OnlusResearch to Prevent BlindnessInternational Foundation for Optic Nerve Diseases (IFOND)Struggling Within Leber'sPoincenot FamilyEierman FoundationNational Eye InstituteUniv Rome, Dept Radiol Oncol & Pathol, Rome, ItalyUniv Bologna, Dept Biomed & NeuroMotor Sci DIBINEM, Bologna, ItalyUniv Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, ItalyBellaria Hosp, IRCCS Ist Sci Neurol Bologna, I-40139 Bologna, ItalyUSC, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA USAUSC, Keck Sch Med, Dept Neurosurg, Los Angeles, CA USAUniv Trieste, Dept Reprod Sci Dev & Publ Hlth, Trieste, ItalyUniv Trieste, IRCCS Burlo Garofolo Children Hosp, Trieste, ItalyNewcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, EnglandFdn Ist Neurol Carlo Besta IRCCS, Unit Mol Neurogenet, Milan, ItalyMRC Mitochondrial Biol Unit, Cambridge, EnglandFed Univ São Paulo UNIFESP, Dept Ophthalmol, São Paulo, BrazilUniv São Paulo, Inst Psychol, Dept Expt Psychol, São Paulo, BrazilStudio Oculist dAzeglio, Bologna, ItalyOsped San Giovanni Evangelista, Tivoli, ItalyAzienda Osped San Camillo Forlanini, Rome, ItalyUniv Rome, Dipartimento Metodi & Modelli Econ Finanza & Terr, Rome, ItalyUniv Rome, Dept Mol Med, Rome, ItalyFed Univ São Paulo UNIFESP, Dept Ophthalmol, São Paulo, BrazilTelethon: GGP06233Telethon: GGP11182Telethon: GPP10005National Eye Institute: EY03040Web of Scienc

Reversible Disruption of Pre-Pulse Inhibition in Hypomorphic-Inducible and Reversible CB1-/- Mice

Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout (-/-) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1-/- mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1-/-) only in absence of doxycycline (Dox). In such mice, under Dox+ or vehicle, as well as in wild-type (WT) and CB1-/-, two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1-/- and IRh-CB1-/- showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1-/- animals, was on the contrary highly and significantly disrupted only in Dox+ IRh-CB1-/- mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1-/- mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1-/- mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders