VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs’ presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon–intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.

Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood–onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.

Early life stress (ELS) refers to harmful environmental events (i.e., poor maternal health, metabolic restraint, childhood trauma) occurring during the prenatal and/or postnatal period, which may cause the ‘epigenetic corruption’ of cellular and molecular signaling of mental and physical development. While the impact of ELS in a wide range of human diseases has been confirmed, the ELS susceptibility to bone diseases has been poorly explored. In this review, to understand the potential mediating pathways of ELS in bone diseases, PRISMA criteria were used to analyze different stress protocols in mammal models and the effects elicited in dams and their progeny. Data collected, despite the methodological heterogeneity, show that ELS interferes with fetal bone formation, also revealing that the stress type and affected developmental phase may influence the variety and severity of bone anomalies. Interestingly, these findings highlight the maternal and fetal ability to buffer stress, establishing a new role for the placenta in minimizing ELS perturbations. The functional link between ELS and bone impairments will boost future investigations on maternal stress transmission to the fetus and, parallelly, help the assessment of catch-up mechanisms of skeleton adaptations from the cascading ELS effects.

Background VDACs (Voltage-Dependent Anion-selective Channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to their presence. In higher eukaryotes three isoforms raised during the evolution: they have the same exon-intron organization and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. Results VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels with a predominance of VDAC1 and VDAC2 over VDAC3. However, RNA-seq CAGE approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription Factor Binding Sites (TFBSs) distribution in the promoters was investigated. The main regulators common to the three VDAC genes were identified as E2FF, NRF1, KLFS, EBOX transcription factors family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each isoform gene were identified, supporting the results in the literature, indicating a general role of VDAC1, as actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. Conclusions For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoforms genes.

PURA syndrome is a congenital developmental disorder caused by de novo mutations in the PURA gene, which encodes a DNA/RNA-binding protein essential for transcriptional and translational regulation. We present the case of an 11-year-old patient with a de novo frameshift variant in the PURA gene, identified through whole exome sequencing (WES). In addition to the classical PURA deficiency phenotype, our patient exhibited pronounced sialorrhea and seizures, which were effectively treated with the ketogenic diet (KD). Our integrative approach, combining a literature review and bioinformatics data, has led to the first documented clinical case showing improvement in both sialorrhea and seizures with KD treatment, a phenomenon not previously reported. Although a direct relationship between the de novo PURA mutation and the KD was not established, we identified a novel frameshift deletion associated with a new clinical phenotype.

Child abuse is a critical social issue. The orthopedic surgeon’s role is essential in noticing signs and symptoms of physical abuse. For this reason, several authors have proposed scoring systems to identify abuse early on and reduce undiagnosed cases. The aim of this systematic review is to overview the screening tools in the literature. In 2021, three independent authors performed a systematic review of two electronic medical databases using the following inclusion criteria: physical child abuse, questionnaire, survey, score, screening tool and predictive tool. Patients who had experienced sexual abuse or emotional abuse were excluded. The risk of bias evaluation of the articles was performed according to the Newcastle–Ottawa Quality Assessment Scale Cohort Studies. Any evidence-level study reporting clinical data and dealing with a physical child abuse diagnosis tool was considered. A total of 217 articles were found. After reading the full texts and checking the reference lists, n = 12 (71,035 patients) articles were selected. A total of seven screening tools were found. However, only some of the seven diagnostic tools included demonstrated a high rate of sensitivity and specificity. The main limits of the studies were the lack of heterogeneity of evidence and samples and the lack of common assessing tools. Despite the multiplicity of questionnaires aimed at detecting validated child abuse, there was not a single worldwide questionnaire for early diagnosis. A combination of more than one test might increase the validity of the investigation.