SCN5A Research Articles

Disruption of asparagine-linked glycosylation to rescue and alter gating of the NaV1.5-Na+ channel.

SCN5A gene encodes the voltage-gated sodium channel NaV1.5 which is composed of a pore-forming α subunit of the channel. Asparagine (N)-linked glycosylation is one of the common post-translational modifications in proteins. The aim of this study was to investigate impact of N-linked glycosylation disruption on the Na+ channel, and the mechanism by which glycosylation regulates the current density and gating properties of the Na+ channel. The NaV1.5-Na+ channel isoform (α submit) derived from human was stably expressed in human embryonic kidney (HEK)-293 cells (Nav1.5-HEK cell). We applied the whole-cell patch-clamp technique to study the impact of N-linked glycosylation disruption in Nav1.5-HEK cell. Inhibition of the N-glycosylation with tunicamycin caused a significant increase of NaV1.5 channel current (INa) when applied for 24h. Tunicamycin shifted the steady-state inactivation curve to the hyperpolarization direction, whereas the activation curve was unaffected. Recovery from inactivation was prolonged, while the fast phase (τfast) and the slow phase (τslow) of the current decay was unaffected by tunicamycin. INa was unaffected by tunicamycin in the present of a proteasome inhibitor MG132 [N-[(phenylmethoxy)carbonyl]-L-leucy-N-[(1S)-1-formyl-3-methylbutyl]-L-leucinamide], while it was significantly increased by tunicamycin in the presence of a lysosome inhibitor butyl methacrylate (BMA). These findings suggest that N-glycosylation disruption rescues the NaV1.5 channel possibly through the alteration of ubiquitin-proteasome activity, and changes gating properties of the NaV1.5 channel by modulating glycan milieu of the channel protein.

Case Series of Early SCN1A-Related Developmental and Epileptic Encephalopathies.

ABSTRACTIntroduction:The developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of rare neurodevelopmental disorders, characterized by early onset seizures that are often intractable, electroencephalographic abnormalities, developmental delay, or regression. The SCN1A pathogenic variants can present as DEE. They are characterized by early infantile seizure onset, profound intellectual disability, and a severe hyperkinetic movement disorder. Studies are lacking, hence we are reporting a case series of early SCN1A-related DEE. The objective of the study was to report clinical and molecular aspects of early SCN1A-related DEE.Materials and Methods:A retrospective chart review of children with DEEs secondary to SCN1A pathogenic variants from January 2015 to March 2020 in a tertiary care referral center from south India.Results:Out of eleven children, seven were boys. The mean age of presentation was 3.5 months. Nine children had seizures triggered by fever. All the children presented with focal and generalized seizures along with epileptic spasms. No focal neurological deficits were noted; routine testing, neuroimaging, and metabolic tests were normal in all the cases. In all the cases, hypsarrhythmia was noted on electroencephalogram (EEG). All the children had pathogenic variants in the SCN1A gene. Five children responded to steroids, one child responded to vigabatrin, and one child responded to stiripentol, but all of them had relapsed and were refractory to other antiepileptic drugs. At follow-up, all children had developmental delays and six of them had autistic features.Conclusion:Early SCN1A-related encephalopathies should be considered in the differential diagnosis of early infantile epileptic encephalopathies. Identification of this condition is important, as treatment and outcome are different from other epileptic encephalopathies.

Association of SCN1A Mutations with Epilepsy among Sudanese Patients

Background: Genetics research of humans has established that a genetic basis contributes to the susceptibility to epilepsy for a majority of the cases. Although many epilepsies are secondary to injury or another illness, approximately 40% are idiopathic, meaning that the original cause is unknown. It is presumed that most idiopathic epilepsies result from genetic abnormalities, with the majority likely caused by mutations in multiple currently unidentified genes. However, research has revealed a growing number of single-gene mutations that cause epilepsy. Objective: To detect some of the genetic mutations which may cause idiopathic epilepsy. Methods: The current study is a cross-sectional study that had been performed at Sheikh Mohamed Khair center, Banat, Omdurman, and National Centre for Neurological Sciences (NCNS) Khartoum state, during the period 2016 to 2019. Ninety-nine participants were enrolled in this study. Demographic data were collected in a predesigned questionnaire blood samples were analyzed for biochemical and molecular tests. Results: Ninety-nine patients diagnosed with idiopathic epilepsy were recruited in this study. The most affected age group was 18 - 40 years accounted for 55% of patients. Females were the majority with 53%. Fifty percent of the patients had the first seizure at age less than 5 years. Ninety percent of the patients have no Family history with epilepsy. All sequenced samples showed genetic mutations, deletion mutation was detected in 71% of the samples. Bioinformatics tools detected a frameshift mutation in the chain of the amino acids. Conclusion: The current study detected deletion mutations in SCN1A gene (frameshift) can cause epilepsy by changing some amino acids with residues that can affect neuronal stability indirectly.

Analysis of SCN1A polymorphism as Genetic Risk Factor for Neurological Disorders

Epileptic seizures lead to changes in the importance of the blood laboratory tests which represent changes in various systems of organs in the body. A present study assessed the association between the rs3812718 polymorphism in SCN1A gene and susceptibility with epilepsy. In total, 48 subjects (28 patients and 20 controls) were included in the study. Subjects’ age and sex were matched. The patients' demographic profiles, including the gender (female: 26 and male; 34), mean of ages (21±8.6), the controls gender (female: 6 and male; 19) and age mean (39±13.3). Single nucleotide polymorphisms (SNPs) was used to investigate the distribution of SCN1A rs3812718 genotypes (G > A) in patients with Epilepsy. Direct sequencing is use to identify the (G>A) polymorphisms of the SCN1A gene on chromosome 2q24. Genotypes and allelic frequencies for the SCN1A in both groups were compared. In addition, the results show two other SNPs for the first time in Iraqi patients rs2217199 T>C and rs3812719 G>T and the study determines some biochemical tests (potassium) were performed by Reflotron and (glucose, sodium, chloride and calcium) by a Spectrophotometer in the sera of subjects. In this population, the alleles frequency of rs2217199/ C, rs3812719/ T, rs3812718/A, the susceptibility of epileptic with gene polymorphisms was correlated (OR = 5.84, p = 0.0001; OR = 4.41, p = 0.001; OR = 5.33, p = 0.001; respectively). The haplotype (CTA) was also significantly related with Epileptic patients (OR = 7.08; p = 0.001). Also, the study showed an increase in glucose levels at p-value= 0.008, normal value in serum K, Cl, Ca and Na levels in Epileptic patient with seizure compare with control. The study in an Iraqi population suggests that SCN1A polymorphisms genetic risk factor for Epileptic patients. Simple blood testing, particularly for some encephalopathies, can be a crucial help for recognizing the etiology.

Genetic cause of epilepsy in a Greek cohort of children and young adults with heterogeneous epilepsy syndromes

We describe a cohort of 10 unrelated Greek patients (4 females, 6 males; median age 6.5 years, range 2-18 years) with heterogeneous epilepsy syndromes with a genetic basis. In these patients, causative genetic variants, including two novel ones, were identified in 9 known epilepsy-related genes through whole exome sequencing. A patient with glycine encephalopathy was a compound heterozygote for the p.Arg222Cys and the p.Ser77Leu AMT variant. A patient affected with Lafora disease carried the homozygous p.Arg171His EPM2A variant. A de novo heterozygous variant in the GABRG2 gene (p.Pro282Thr) was found in one patient and a pathogenic variant in the GRIN2B gene (p.Gly820Val) in another patient. Infantile-onset lactic acidosis with seizures was associated with the p.Arg446Ter PDHX gene variant in one patient. In two additional epilepsy patients, the p.Ala1662Val and the novel non-sense p.Phe1330Ter SCN1A gene variants were found. Finally, in 3 patients we observed a novel heterozygous missense variant in SCN2A (p.Ala1874Thr), a heterozygous splice site variant in SLC2A1 (c.517-2A>G), as a cause of Glut1 deficiency syndrome, and a pathogenic variant in STXBP1 (p.Arg292Leu), respectively. In half of our cases (patients with variants in the GRIN2B, SCN1A, SCN2A and SLC2A1 genes), a genetic cause with potential management implications was identified.

Congenital insensitivity to pain with anhidrosis and compensatory hyperhidrosis

Hereditary sensory and autonomic neuropathy is a rare syndrome characterized by congenital insensitivity to pain, temperature changes, and an autonomic nerve formation disorder. We report an 8-year-old boy who presented with late-onset of self-mutilating behavior, insensitivity to pain, temperature, and anhidrosis with compensatory hyperhidrosis. Exome sequencing revealed a mutation of the SCN9A gene at chromosome 2 with nucleotide change c. G554A/p. Arg185His at exon 5 along with HSPB1 mutation at chromosome 5.

Relative Quantification of NaV1.1 Protein in Mouse Brains Using a Meso Scale Discovery-Electrochemiluminescence (MSD-ECL) Method.

Densitometric analysis is often used to quantify NaV1.1 protein on immunoblots, although the sensitivity and dilution linearity of the method are usually poor. Here we present a protocol for quantification of NaV1.1 in mouse brain tissues using a Meso Scale Discovery-Electrochemiluminescence (MSD-ECL) method. MSD-ECL is based on ELISA (enzyme-linked immunosorbent assay) and uses electrochemiluminescence to produce measurable signals. Two different antibodies are used in this assay to capture and detect NaV1.1 respectively in brain tissue lysate. The specificity of the antibodies is confirmed by Scn1a gene knock-out tissue. The calibration curve standards used in this assay were generated with mouse liver lysate spiked with mouse brain lysate, instead of using a recombinant protein. We showed that this method was qualified and used for quantification of NaV1.1 in mouse brain tissues with specificity, accuracy and precision.

Combined Antiseizure Efficacy of Cannabidiol and Clonazepam in a Conditional Mouse Model of Dravet Syndrome.

Dravet Syndrome (DS) is a severe childhood epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene encoding brain type-I voltage-gated sodium channel Nav1.1. DS is a devastating disease that typically begins at six to nine months of age. Symptoms include recurrent intractable seizures and premature death with severe neuropsychiatric comorbidities, including hyperactivity, sleep disorder, anxiety-like behaviors, impaired social interactions, and cognitive deficits. There is an urgent unmet need for therapeutic approaches that control and cure DS, as available therapeutic interventions have poor efficacy, intolerance, or other side effects. Here we investigated the therapeutic potential of combining the benzodiazepine clonazepam (CLZ) with the nonpsychotropic phytocannabinoid cannabidiol (CBD) against thermally induced febrile seizures in a conditional mouse model of DS. Our results show that a low dose of CLZ alone or combined with CBD elevated the threshold temperature for the thermal induction of seizures. Combination of CLZ with CBD significantly reduced seizure duration compared to the vehicle or CLZ alone, but did not affect seizure severity, indicating potential additive actions of CLZ and CBD on the duration of seizures. Our findings provide preclinical evidence supporting combination therapy of CLZ and CBD for treatment of febrile seizures in DS.

Возможная физиологическая функция эндогенного уабаина

Our results suggest that endogenous ouabain triggers two different signaling processes. The first, fast process, modulates the activation gating device of the NaV1.8 channels, thereby reducing their functional activity. The second, slow process, decreases the density of NaV1.8 channels in the membrane of the primary sensory neuron. We assume that in this case, endogenous ouabain triggers a downstream cascade leading to a decrease in the expression of the SCN10A gene that produces NaV1.8 channels. It can be concluded that endogenous ouabain, when it interacts with the primary sensory neuron, performs important function of modulating functional activity of NaV1.8 channels. The practical result of the study was the assumption that the delivery of ouabain as a drug substance to the membrane of a nociceptive neuron in nanomolar concentration should lead to a safe and effective antinociceptive action of this agent at the organismal level.

SCN2A基因突变相关的癫痫研究进展

SCN2A基因突变相关的癫痫研究进展

Presunta parálisis periódica hipercalémica con miotonía en perros Shi-Tzú y Pastor Alemán

En los humanos, las canalopatías del músculo esquelético son entidades de base genética y de incidencia muy baja. En relación al canal de sodio en particular, las diferentes mutaciones SCN4A pueden dar lugar a diversos fenotipos que van desde la parálisis muscular (parálisis periódica hipercalémica, parálisis periódica hipocalémica) a la hiperexcitabilidad muscular (paramiotonía congénita, miotonías agravadas por potasio), pasando por fenotipos combinados de las dos anteriores. Existe una estrecha interrelación entre la parálisis periódica hipercalémica y las miotonías; ambas características pueden coexistir en el mismo paciente.Este trabajo describe un cuadro clínico que afectó a una camada de 7 cachorros Pastor Alemán y a una camada de 4 cachorros Shi-Tzú, con episodios caracterizados por un fenotipo clínico de parálisis muscular combinado con hiperexcitabilidad muscular.De acuerdo a los hallazgos clínicos (fenomenología clínica, edad de aparición, recurrencia de los episodios, ausencia de signos clínicos entre los episodios) y de laboratorio (hipercalemia), y a los resultados del tratamiento con acetazolamida, el diagnóstico presuntivo fue parálisis periódica hipercalémica con miotonía/paramiotonía por una canalopatía SCN4A.Destacamos la importancia del diagnóstico clínico para estas raras patologías. En ausencia de diagnóstico genético, los métodos de diagnóstico complementario tiene valor limitado debido al carácter funcional de estos trastornos.Proponemos esta comunicación como la primera de este tipo en perros de raza Pastor Alemán y Shi-Tzú. In humans, skeletal muscle channelopathies are genetic disease with very low incidence. Regarding the sodium channel in particular, the different SCN4A mutations can result in various phenotypes ranging from muscle paralysis (hyperkalemic periodic paralysis, hypokalemic periodic paralysis) to muscle hyperexcitability (congenit paramyotonia, myotonias aggravated by potassium), through combined phenotypes of the previous two. There is a close interrelation between hyperkalemic periodic paralysis and myotonias; both characteristics can coexist in the same patient.This work describes a clinical picture affecting a litter of 7 German Shepherd puppies and a litter of 4 Shih-Tzu puppies with episodes characterized by a clinical phenotype of muscular paralysis combined with muscular hyperexcitability.Based on clinical findings (clinical phenomenology, age of onset, episodic recurrence, absense of clinical signs in the period between episodes) and laboratory (hyperkalemia), and the results of treatment with acetazolamide, the presumptive diagnosis was hyperkalemic periodic paralysis with myotonia/paramyotonia due to SCN4A channelopathy.We emphasize the importance of clinical diagnosis for these rare pathologies. In absence of genetic diagnosis, complementary diagnostic methods have limited value due to the functional nature of these disorders.We proposed this description as the first communication of this type in German Shepherd and Shi-Tzu dogs.

A novel mutation of SCN4A gene causes hypokalemic periodic paralysis in a Chinese family

Objective: To report a Chinese family with hypokalemic periodic paralysis (HOKPP) and investigate the clinical and pathogenic gene characteristics of the family. Methods: The clinical, electrophysiological and pathological data of the proband of the family were analyzed, and the information of the family was investigated in detail. The peripheral venous blood of the six members of the family was collected and their genomic DNA was extracted. The genes related to periodic paralysis analysis of the proband were performed by the second generation sequencing. The pathogenicity of the mutant protein was respectively analyzed by the bioinformatics software SIFT, Polyphen2 and Mutation Tasker. The cosegregation analysis of phenotype and genotype of the family was performed by the first generation sequencing. Results: There were 3 patients in the family with the onset age of 21 to 42 years old. All the patients manifested with vomiting as the first symptoms, then presented with muscle weakness accompanied by muscle soreness. The muscle weakness gradually relieved in 3 to 5 days. Creatine kinase (CK) of the proband significantly increased. Electromyographic exercise test was positive, however, electromyography and muscle pathological analysis were normal. The genes related to periodic paralysis analysis of the proband found a novel mutation (c.2458A>T (p.N.820Y)) of SCN4A gene which was located in the conservative region. The function analysis showed it was a pathogenic mutation. Moreover, the first generation sequencing confirmed that the mutation was cosegregated with patients in the family. Meanwhile, it was found that the proband's son carried the same mutation, but without any symptom, indicating that he was a pre-symptomatic patient. Conclusions: Vomiting can be one of the symptoms of the patients with HOKPP. The novel mutation of SCN4A gene c.2458 A>T is the pathogenic mutation of the family. Patients with periodic paralysis should be tested for blood potassium and genes as early as possible to facilitate early diagnosis and genetic counseling.

Developmental alterations in firing properties of hippocampal CA1 inhibitory and excitatory neurons in a mouse model of Dravet syndrome

Dravet syndrome (Dravet) is a rare, severe childhood-onset epilepsy, caused by heterozygous de novo mutations in the SCN1A gene, encoding for the alpha subunit of the voltage-gated sodium channel, NaV1.1. The neuronal basis of Dravet is debated, with evidence favoring reduced function of inhibitory neurons, that might be transient, or enhanced activity of excitatory cells. Here, we utilized Dravet mice to trace developmental changes in the hippocampal CA1 circuit, examining the properties of CA1 horizontal stratum-oriens (SO) interneurons and pyramidal neurons, through the pre-epileptic, severe and stabilization stages of Dravet. Our data indicate that reduced function of SO interneurons persists from the pre-epileptic through the stabilization stages, with the greatest functional impairment observed during the severe stage. In contrast, opposing changes were detected in CA1 excitatory neurons, with a transient increase in their excitability during the pre-epileptic stage, followed by reduced excitability at the severe stage. Interestingly, alterations in the function of both inhibitory and excitatory neurons were more pronounced when the firing was evoked by synaptic stimulation, implying that loss of function of NaV1.1 may also affect somatodendritic functions. These results suggest a complex pathophysiological mechanism and indicate that the developmental trajectory of this disease is governed by reciprocal functional changes in both excitatory and inhibitory neurons.

Whole exome sequencing identified a novel myopalladin gene mutation in a cardiomyopathy patient

Cardiomyopathies (CMs) are a heterogenous group of disorders that affects the heart muscle. Incardiomyopathies, phenotypic overlapping among the inherited cardiovascular diseases (CVDs) limits theability to establish a diagnosis based solely on clinical features. Here, we developed a next generationsequencing (NGS) assay to analyze a panel of 142 known cardiomyopathy genes in 9 Vietnamese patientsfrom Children Hospital 2, Hochiminh City and Medical University Hospital, Hochiminh City, Vietnam.Whole exome sequencing (WES) - a technique which determines the variations of all coding regions (exons)of the known genes - validated a total of 65 rare variants in 18 cardiomyopathy genes among the studiedVietnamese unrelated patients. Of 65 variants identified, 28 variants were homozygous and the other 37 oneswere heterozygous. Among the 65 variants, TTN gene variants accounted the most for 13 mutations, which areknown to be benign. Other groups of 9 and 8 mutations belong to SYNE1 and MYPN genes, respectively. Tenout of 65 mutations distributed equally to NDUFV2 and SCN5A gene variants. We detected 6 and 4 variantsfor SYNE2 and COX15 genes, respectively. Each gene of DMD, KCNE1, NEBL and RBM20 has 2 variants. Asingle variant was detected for AKAP9, CAV3, DSC2, DSG2, DSP, MYBPC3 and MYH6 genes. Especially,among them, we found a novel heterozygous nonsynonymous mutation c.1527C>G on the MYPN gene. Thesegenetic results support the “pan-cardiomyopathy panel” approach, by which the molecular diagnosis ofcardiomyopathies, early identification of arrhythmia development and better clinical management ofcardiomyopathic patients are applied.

High genetic burden in 163 Chinese children with status epilepticus

PurposeThis study aimed to investigate the genetic aetiology in Chinese children diagnosed with status epilepticus (SE). MethodsNext-generation sequencing, copy number variation (CNV) analysis, and other genetic testing methods were conducted for children with SE lacking an identifiable non-genetic aetiology. Furthermore, the phenotype and molecular data of patients with SE were retrospectively analysed. ResultsAmong children with SE lacking an identifiable non-genetic aetiology, 73 out of 163 children (44.8 %) were found to have causative variants associated with SE including 66 monogenic mutations in 22 genes and 7 CNVs. Based on the American College of Medical Genetics and Genomics scoring system, the monogenic variants included 64 pathogenic/likely pathogenic and 2 uncertain significance variants. SCN1A gene mutations (n = 32) were the most common cause, followed by TSC2 (n = 5), CACNA1A (n = 5), SCN2A (n = 4), SCN9A (n = 2) and DEPDC5 (n = 2) gene mutations. Sixteen mutations were identified in single genes. Furthermore, 51 (77.3 %) monogenic mutations were de novo. Age at SE onset < 1 year (odds ratio [OR] = 2.70, 95 % confidence interval [CI]: 1.25–5.83, p = 0.012) and co-morbidity of intellectual disability (OR = 3.36, 95 %CI: 1.61–6.99, p = 0.001) were independently associated with pathogenic genetic variants. ConclusionThis study identified genetic aetiology in 44.8 % of patients with SE, which indicates a high burden of genetic aetiology among children with SE in China. Our findings highlight the importance for genetic testing of children with SE that lacks an identifiable non-genetic aetiology.

No association between SCN9A and monogenic human epilepsy disorders.

Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications.

Characterization of an N-terminal Nav1.5 channel variant \u2013 a potential risk factor for arrhythmias and sudden death?

BackgroundAlterations in the SCN5A gene encoding the cardiac sodium channel Nav1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance.MethodsMutant as well as wild type GFP tagged Nav1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique.ResultsElectrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Nav1.5 current over the entire voltage window.ConclusionThe results support the assumption that the detected sequence aberration alters Nav1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.

Role of Non-Coding Variants in Brugada Syndrome.

Brugada syndrome (BrS) is an inherited electrical heart disease associated with a high risk of sudden cardiac death (SCD). The genetic characterization of BrS has always been challenging. Although several cardiac ion channel genes have been associated with BrS, SCN5A is the only gene that presents definitive evidence for causality to be used for clinical diagnosis of BrS. However, more than 65% of diagnosed cases cannot be explained by variants in SCN5A or other genes. Therefore, in an important number of BrS cases, the underlying mechanisms are still elusive. Common variants, mostly located in non-coding regions, have emerged as potential modulators of the disease by affecting different regulatory mechanisms, including transcription factors (TFs), three-dimensional organization of the genome, or non-coding RNAs (ncRNAs). These common variants have been hypothesized to modulate the interindividual susceptibility of the disease, which could explain incomplete penetrance of BrS observed within families. Altogether, the study of both common and rare variants in parallel is becoming increasingly important to better understand the genetic basis underlying BrS. In this review, we aim to describe the challenges of studying non-coding variants associated with disease, re-examine the studies that have linked non-coding variants with BrS, and provide further evidence for the relevance of regulatory elements in understanding this cardiac disorder.

PNA-Based Graphene Oxide/Porous Silicon Hybrid Biosensor: Towards a Label-Free Optical Assay for Brugada Syndrome.

Peptide nucleic acid (PNA) is a synthetic DNA mimic that outperforms the properties of traditional oligonucleotides (ONs). On account of its outstanding features, such as remarkable binding affinity towards complementary DNA or RNA as well as high thermal and chemical stability, PNA has been proposed as a valuable alternative to the ON probe in gene-sensor design. In this study, a hybrid transducer made-up of graphene oxide (GO) nano-sheets covalently grafted onto a porous silicon (PSi) matrix has been investigated for the early detection of a genetic cardiac disorder, the Brugada syndrome (BS). A functionalization strategy towards the realization of a potential PNA-based device is described. A PNA, able to detect the SCN5A gene associated with the BS, has been properly synthesized and used as a bioprobe for the realization of a proof-of-concept label-free optical PNA-biosensor. PSi reflectance and GO photoluminescence signals were simultaneously exploited for the monitoring of the device functionalization and response.

Generation of iPSC lines from two patients affected by febrile seizure due to inherited missense mutation in SCN1A gene.

Here, we described the generation of human induced pluripotent stem cell lines (hiPSCs) from fibroblasts isolated by punch biopsies of two siblings carrying inherited mutation (c.434T>C) in the SCN1A gene, encoding for the neuronal voltage gated sodium channel NaV1.1. The mutation leads to the substitution of a highly conserved methionine with a threonine (M145T) in the protein sequence, leading to infant febrile seizures (FS). The older brother, affected by complex FS, also developed temporal lobe epilepsy (TLE) during adolescence.