Molecular and phenotypical findings of a novel de novo SYNGAP1 gene variant in an 11-year-old Iranian boy with intellectual disability.

OBJECTIVE: Intellectual developmental disorder (IDD) type 5 is an autosomal dominant (AD) disorder and is characterized by intellectual disability (ID), psychomotor developmental delay, variable autism phenotypes, microcephaly, and seizure. IDD can be caused by mutations in the SYNGAP1 gene, which encodes a Ras GTPase-activating protein. This study revealed a novel de novo nonsense variant in SYNGAP1. The identification of such variants is essential for genetic counseling in patients and their families. METHODS: Exome sequencing implicated the causative variant. Sanger sequencing and cosegregation analyses were used to confirm the variant. Multiple in silico analysis tools were applied to interpret the variant using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: The de novo NM_006772.3(SYNGAP1):c.3685C>T variant was identified in an 11-year-old boy with severe intellectual disability, neurodevelopmental delay, speech disorder, ataxia, specific dysmorphic facial features, and aggressive behavior. CONCLUSION: The current study findings expand the existing knowledge of variants in SYNGAP1 that have been previously associated with nonsyndromic intellectual disability and autism, extending the spectrum of phenotypes associated with this gene. The data have implications for genetic diagnosis and counseling in similar phenotypic presentations.

A data-driven network decomposition of the temporal, spatial, and spectral dynamics underpinning visual-verbal working memory processes.

The brain dynamics underlying working memory (WM) unroll via transient frequency-specific large-scale brain networks. This multidimensionality (time, space, and frequency) challenges traditional analyses. Through an unsupervised technique, the time delay embedded-hidden Markov model (TDE-HMM), we pursue a functional network analysis of magnetoencephalographic data from 38 healthy subjects acquired during an n-back task. Here we show that this model inferred task-specific networks with unique temporal (activation), spectral (phase-coupling connections), and spatial (power spectral density distribution) profiles. A theta frontoparietal network exerts attentional control and encodes the stimulus, an alpha temporo-occipital network rehearses the verbal information, and a broad-band frontoparietal network with a P300-like temporal profile leads the retrieval process and motor response. Therefore, this work provides a unified and integrated description of the multidimensional working memory dynamics that can be interpreted within the neuropsychological multi-component model of WM, improving the overall neurophysiological and neuropsychological comprehension of WM functioning.

The spectral slope as a marker of excitation/inhibition ratio and cognitive functioning in multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission and potentially cognitive impairment. Current methods for measuring the excitation/inhibition (E/I) ratio are mostly invasive, but recent research combining neurocomputational modeling with measurements of local field potentials has indicated that the slope with which the power spectrum of neuronal activity captured by electro- and/or magnetoencephalography rolls off, is a non-invasive biomarker of the E/I ratio. A steeper roll-off is associated with a stronger inhibition. This novel method can be applied to assess the E/I ratio in people with multiple sclerosis (pwMS), detect the effect of medication such as benzodiazepines, and explore its utility as a biomarker for cognition. We recruited 44 healthy control subjects and 95 pwMS who underwent resting-state magnetoencephalographic recordings. The 1/f spectral slope of the neural power spectra was calculated for each subject and for each brain region. As expected, the spectral slope was significantly steeper in pwMS treated with benzodiazepines (BZDs) compared to pwMS not receiving BZDs (p = .01). In the sub-cohort of pwMS not treated with BZDs, we observed a steeper slope in cognitively impaired pwMS compared to cognitively preserved pwMS (p = .01) and healthy subjects (p = .02). Furthermore, we observed a significant correlation between 1/f spectral slope and verbal and spatial working memory functioning in the brain regions located in the prefrontal and parietal cortex. In this study, we highlighted the value of the spectral slope in MS by quantifying the effect of benzodiazepines and by putting it forward as a potential biomarker of cognitive deficits in pwMS.

A Homozygous Nonsense Variant in UVSSA Causes UV-sensitive Syndrome from Very Large Kindred: The First Report from Iran.

Background: Recessive disruptive mutations in nucleotide excision repair genes are responsible for a wide range of cutaneous photosensitivity and, in some cases, are associated with multi-system involvement. The heterogeneous nature of these conditions makes next-generation sequencing the method of choice to detect disease-causing variants. Materials and Methods: A patient from a large multiplex inbred Iranian kindred with several individuals suffering from skin sun-sensitive manifestations underwent complete clinical and molecular evaluations. Whole exome sequencing (WES) was performed on the genomic sample of the proband, followed by bioinformatics analysis. Subsequently, co-segregation of the candidate variant with the condition was performed by Sanger sequencing. Results: A rare homozygous nonsense variant, c.1040G>A (p. Trp347*), was identified in the UVSSA gene, resulting in UV-sensitive syndrome (UVSS) complementation group A. The global minor allele frequency of the variant is < 0.001 in population databases. Tryptophan 347 residue is conserved among mammalians and vertebrates, and the null variant is believed to lead to a truncated protein with cellular mislocalization. Conclusions: Here, we report the first genetic diagnosis of UVSS-A in Iran via the successful application of Next-generation sequencing, which expands our understanding of the molecular pathogenesis of this condition.

Polyurethane and polyurethane/hydroxyapatite scaffold in a three-dimensional culture system.

Designing a new scaffold with an optimal ability of osteogenesis differentiation is a significant step bone tissue engineering along with the growing demands for bone craft in recent decades. Herein, we used Polyurethane (PU), a novel biocompatible and flexible polymer, and Hydroxyapatite (HA), the major component of human hard tissues matrix for developing new scaffolds and analyzing the in vitro osteogenic differentiation potential of human adipose-derived mesenchymal stem cells (Ad-MSCs) in basal and induction media. Gene expression analysis was performed to evaluate the expression level of four osteogenic differentiation genes. MTT assays were also done to assess the attachment and proliferation of the cells after 7 and 21 days of seeding to scaffolds. The expression level of RUNX2 was increased in seeded cells on PU/HA scaffolds compared with the PU. Cellular adhesion and proliferation of the Ad-MSCs were higher in PU/HA than PU scaffolds according to the histology analysis. The PU and PU/HA scaffolds supported the attachment, proliferation, and differentiation of Ad-MSCs, and they are suitable candidates for producing constructs in bone regeneration. However, further in-vitro and in-vivo studies on these scaffolds are needed to introduce an appropriate candidate for clinical bone regeneration.

Expression of TRPV1 as A Heat Sensitive Voltage-Dependent Ion Channel and Oxidative Stress in Sperm Samples of Infertile Men with Varicocele: A Case-Control Study.

Objective: Transient receptor potential vanilloid 1 (TRPV1) is a heat-activated nonselective cation channel that plays important role in the spermatogenesis, capacitation, acrosome reaction and sperm/oocyte fusion. Considering the high testicular temperature and oxidative stress in varicocele condition, we aimed to assess expression of TRPV1 in sperm of infertile men. Materials and Methods: In this case-control study, twenty-five men with varicocele (grade II and III) as well as twentyfive fertile were recruited. Sperm parameters, protamine deficiency (Chromomycin A3), DNA damage (TUNEL), lipid peroxidation (BODIPY), TRPV1 gene expression (real time polymerase chain reaction), TRPV1 protein (flowcytometry and immunocytochemical techniques), and acrosome reaction were assessed between fertile and varicocele groups. Results: We observed a significant decrease in the sperm parameters, and also, an increased DNA damage, lipid peroxidation, and protamine deficiency in varicocele group. Although, the mRNA expression of TRPV1 was similar between varicocele and fertile groups, its expression at the protein level was significantly decreased in the varicocele group in comparison with fertile group. Additionally, the TRPV1 localization was changed from the equatorial region to the acrosomal region of the head, especially in the acrosomal region, which was more significant in the fertile group than the varicocele group after inducing acrosome reaction. Conclusion: In addition to the quality of sperm parameters, and chromatin integrity that were lower significantly in varicocele group, the expression of TRPV1 protein was also lower in varicocele condition that could be associated with reduced capacitation, acrosome reaction and sperm/oocyte fusion and thereby infertility.

Down-Regulated Expression of Cystathionine ß-Synthase and Cystathionine γ-Lyase in Varicocele, and Infertile Men: A Case-Control Study.

Objective: Cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE) are two important enzymes involved in One-Carbon metabolism. These enzymes play important roles in modulating oxidative stress and inflammation in male factor infertility through participating in the synthesis of glutathione (GSH) antioxidants in the trans-sulfuration pathway. Besides, the direct release of hydrogen sulfide (H2S) has anti-inflammatory and antioxidant effects. Therefore, the expression of CBS and CSE genes at mRNA levels in infertile and varicocele men was evaluated and compared to the healthy counterparts to clarify their possible role in the pathology of male infertility. Materials and Methods: In this case-control study, semen parameter assessment (concentration, morphology, and motility of sperms) was performed on 28 men with varicocele, 43 infertile men with abnormal sperm parameters, and 19 fertile men. RNA was extracted from sperm samples followed by cDNA synthesis and real-time polymerase chain reaction (PCR) using CBS, CSE, and GAPDH primers. Results: Sperm concentration and motility in infertile and varicocele groups were significantly lower (P=0.001), while spermatoza normal morphology was higher than fertile group (P=0.05). The expression levels of both CBS and CSE genes in infertile (P=0.04 and P=0.037 respectively) and varicocele (P=0.01 and P=0.046 respectively) groups were significantly lower than fertile group. Additionally, CBS gene expression indicated a positive correlation with expression of CBS gene (r=0.296, P=0.025) and sperm parameters. Conclusion: In light of our findings, there is a valid rationale to consider the primary role of CBS and CSE enzymes impairment in male factor infertility which specifically may point to a deficit in the release of essential antioxidants including the H2S as a molecular basis of infertility and warrants further investigation.

A Computational Framework to Infer Prostate Cancer-Associated Long Noncoding RNAs and Analyses for Identifying a Competing Endogenous RNA Network.

Background: Prostate cancer (PC) is the second leading cause of cancer death after lung cancer in men. Current biomarkers are ineffective for the treatment and management of the disease. Long noncoding RNAs (lncRNAs) are a heterogeneous group of transcripts that are involved in complex gene expression regulatory networks. Although lncRNAs have been suggested to be promising as future biomarkers, the connection between the majority of lncRNAs and human disease remains to be elucidated. One approach to elucidate the roles of lncRNAs in disease is through the development of computational models. For example, a novel computational model termed HyperGeometric distribution for LncRNA-Disease Association (HGLDA) has been developed. Such models need to be developed on a tumor-specific basis to better suit the particular problem. Methods: In this study, we constructed a potential pipeline through two models, HGLDA and pathway-based using data from several databases. To validate the obtained data, the expression levels of selected lncRNAs were investigated quantitatively in the DU-145, LNCaP, and PC3 PC cell lines using quantitative real-time PCR. Results: We obtained a number of lncRNAs from both models, many of which were filtered through several databases that ultimately resulted in identification of six high-value lncRNA targets. Their expression was correlated with one important component of the PI3K pathway, known to be related to PC. Conclusion: Through the assembly of a lncRNA-miRNAs-mRNA competing endogenous RNA network, we successfully predicted lncRNAs interfering with miRNAs and coding genes related to PC.

Effect of Different High-Fat and Advanced Glycation End-Products Diets in Obesity and Diabetes-Prone C57BL/6 Mice on Sperm Function.

BACKGROUND: We aimed to compare the effects of using high-fat (HF) and advanced glycation end-products (AGEs) containing dietsto induce obesity and diabetes on sperm function in mice. MATERIALS AND METHODS: In this experimental study, twenty-five 4-week old C57BL/6 mice were divided into 5 groups and were fed with control, 45% HF, 60% HF, 45% AGEs-HF, or 60% AGEs-HF diet. After 28 weeks, fast blood sugar, glucose intolerance, insulin concentration, homeostatic model assessments (HOMA) for insulin resistance (IR) and HOMA for beta cells (HOMA beta) from systematic blood were assessed. In addition, body weight, morphometric characteristics of testes, sperm parameters, DNA damage (AO), protamine deficiency (CMAA3), and sperm membrane (DCFH-DA) and intracellular (BODIPY) lipid peroxidation were measured. RESULTS: Body mass and fasting blood sugar increased significantly in all experimental groups compared to the control group. Insulin concentration, glucose intolerance, HOMA IR, and HOMA beta were also increased significantly with higher levels of fat and AGEs in all four diets (P<0.05). The changes in the 60% HF-AGEs group, however, were more significant (P<0.001). Morphometric characteristics of the testis, sperm concentration, and sperm morphology in the diet groups did not significantly differ from the control group, while sperm motility and DNA damage in the 45%HF were significantly low. Although for protamine deficiency, both 60% HF-AGEs and 45% HF showed a significant increase compared to the control, the mean of sperm lipid in the 45% HF group and intracellular peroxidation in the 60% HF-AGEs group had the highest and the lowest increases, respectively. CONCLUSION: Our results, interestingly, showed that isthe negative effects of a diet containing AGEs on examined parameters are lessthan those in HF diets. One possible reason is detoxification through the activation of the protective glyoxalase pathway asthe result of the chronic AGEs increase in the body.

A report of pregnancy following ICSI in one of two sisters with familiar primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a disorder of structure and function of motor ciliary and dyskinetic activity of ciliary in the fallopian tubes of affected women and could lead to infertility in some cases. In vitro fertilisation (IVF) is a choice of treatment in infertile women with PCD, which could conquer the tubal dysfunction. In this case study, we report a PCD affected woman with infertility who was treated by IVF and pregnancy was achieved but it failed due to the spontaneous abortion. We also performed whole-exome sequencing for this case and her PCD-affected sister, which did not reveal any genetic abnormality related to the PCD or infertility.

Upregulation of MTOR, RPS6KB1, and EIF4EBP1 in the whole blood samples of Iranian patients with multiple sclerosis compared to healthy controls.

Various genetic and epigenetic mechanisms have been suggested to play roles as the underlying pathophysiology of Multiple Sclerosis (MS). Changes in different parts of the mTOR signaling pathway are among the potential suggested mechanisms based on the specific roles of this pathway in CNS. MTOR, RPS6KB1, and EIFEBP1 genes are among important genes in the mTOR pathway, responsible for the proper function of acting proteins in this signaling pathway. This study aimed to investigate the relative expression levels of these genes in the blood samples of relapsing-remitting MS (RRMS) patients compared to healthy controls. In this case-control study blood samples were collected from 30 newly diagnosed RRMS patients and 30 age and sex-matched healthy controls. mRNA level of MTOR, RPS6KB1, and EIFEBP1 genes were assessed using Real-Time PCR. The expression of MTOR, RPS6KB1, and EIF4EBP1 genes was up regulated in MS patients compared to healthy controls (p < 0.001 for all mentioned genes). Considering gender differences, expression of the mentioned genes was increased among female patients (all P < 0.001). However, no statistically significant changes were observed among male patients. Based on the receiver operating characteristic, MTOR gene had the highest diagnostic value followed by EIF4EBP1 and RPS6KB1 genes in differentiating RRMS patients from controls. In conclusion, we found the simultaneous upregulation of MTOR, RPS6KB1, and EIF4EBP1 genes among RRMS patients. MTOR showed to have the highest diagnostic value compared to other 2 genes in differentiating RRMS patients. Further studies evaluating the importance of these findings from pharmacological and prognostic perspectives are necessary.