Genetic correction of Werner syndrome gene reveals impaired pro-angiogenic function and HGF insufficiency in mesenchymal stem cells.

WRN mutation causes a premature aging disease called Werner syndrome (WS). However, the mechanism by which WRN loss leads to progeroid features evident with impaired tissue repair and regeneration remains unclear. To determine this mechanism, we performed gene editing in reprogrammed induced pluripotent stem cells (iPSCs) derived from WS fibroblasts.

Toward a Pathway-Driven Clinical-Molecular Framework for Classifying Autism Spectrum Disorders.

Background: The current classification system of neurodevelopmental disorders is based on clinical criteria; however, this method alone fails to incorporate what is now known about genomic similarities and differences between closely related clinical neurodevelopmental disorders. Here we present an alternative clinical molecular classification system of neurodevelopmental disorders based on shared molecular and cellular pathways, using syndromes with autistic features as examples.

Methods: Using the Online Mendelian Inheritance in Man database, we identified 83 syndromes that had "autism" as a feature of disease, which in combination were associated with 69 autism disease-causing genes.

Functional genomics analysis of Phelan-McDermid syndrome 22q13 region during human neurodevelopment.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS.

Barakat syndrome revisited.

Barakat syndrome also known as HDR syndrome (Online Mendelian Inheritance in Man [OMIM] 146255), was first described by Barakat et al. in . It is a rare genetic disorder characterized by the triad of hypoparathyroidism "H," sensorineural deafness "D," and renal disease "R.

Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome.

Objective: Phelan-McDermid Syndrome (PMS) is a rare genetic condition associated with loss of function mutations, including deletions, in the chromosome 22q13 region. This PMS phenotype includes intellectual disability, often minimal to absent verbal skills, and other neurologic features including autism spectrum disorder and seizures. Reports indicate seizures and abnormal electroencephalograms (EEGs) in this population, but previous studies do not describe EEG findings during sleep or prognostic value of abnormal EEG over any time period.

Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons.

Autism spectrum disorder is a complex neurodevelopmental disorder whose pathophysiology remains elusive as a consequence of the unavailability for study of patient brain neurons; this deficit may potentially be circumvented by neural differentiation of induced pluripotent stem cells. Rare syndromes with single gene mutations and autistic symptoms have significantly advanced the molecular and cellular understanding of autism spectrum disorders; however, in aggregate, they only represent a fraction of all cases of autism. In an effort to define the cellular and molecular phenotypes in human neurons of non-syndromic autism, we generated induced pluripotent stem cells (iPSCs) from three male autism spectrum disorder patients who had no identifiable clinical syndromes, and their unaffected male siblings and subsequently differentiated these patient-specific stem cells into electrophysiologically active neurons.

The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants.

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

Objective: Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed.

A Non-inflammatory Role for Microglia in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, difficulties with language, and repetitive/restricted behaviors. The etiology of ASD is still largely unclear, but immune dysfunction and abnormalities in synaptogenesis have repeatedly been implicated as contributing to the disease phenotype. However, an understanding of how and if these two processes are related has not firmly been established.

Hypermethylation of genes in testicular embryonal carcinomas.

Background: Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation.

Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD.

The autistic brain in the context of normal neurodevelopment.

The etiology of autism spectrum disorders (ASDs) is complex and largely unclear. Among various lines of inquiry, many have suggested convergence onto disruptions in both neural circuitry and immune regulation/glial cell function pathways. However, the interpretation of the relationship between these two putative mechanisms has largely focused on the role of exogenous factors and insults, such as maternal infection, in activating immune pathways that in turn result in neural network abnormalities.

GermlncRNA: a unique catalogue of long non-coding RNAs and associated regulations in male germ cell development.

Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date.

Prefrontal cortex hemodynamics and age: a pilot study using functional near infrared spectroscopy in children.

Cerebral hemodynamics reflect cognitive processes and underlying physiological processes, both of which are captured by functional near infrared spectroscopy (fNIRS). Here, we introduce a novel parameter of Oxygenation Variability directly obtained from fNIRS data -the OV Index-and we demonstrate its use in children. fNIRS data were collected from 17 children (ages 4-8 years), while they performed a standard Go/No-Go task.

Modulation of microRNA expression in human lung cancer cells by the G9a histone methyltransferase inhibitor BIX01294.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of their target genes at the post-transcriptional level. In cancer cells, miRNAs, depending on the biological functions of their target genes, may have a tumor-promoting or -suppressing effect. Treatment of cancer cells with inhibitors of DNA methylation and/or histone deacetylation modulates the expression level of miRNAs, which provides evidence for epigenetic regulation of miRNA expression.

Telomerase protects werner syndrome lineage-specific stem cells from premature aging.

Werner syndrome (WS) patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction.

Long noncoding RNAs in spermatogenesis: insights from recent high-throughput transcriptome studies.

Spermatogenesis is a complex developmental process in which undifferentiated spermatogonia are differentiated into spermatocytes and spermatids through two rounds of meiotic division and finally giving rise to mature spermatozoa (sperm). These processes involve many testis- or male germ cell-specific gene products that undergo strict developmental regulations. As a result, identifying critical, regulatory genes controlling spermatogenesis provide the clues not only to the regulatory mechanism of spermatogenesis at the molecular level, but also to the identification of candidate genes for infertility or contraceptives development.

Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum.

Background: The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies.

Mapping genomic features of tiling microarray data by TileMapper.

The recent revolution of genomics techniques has allowed the detection of various sequence features and biological variations on whole-genome scale. However, these high-resolution data present significant challenges for experimental biologists to understand and analyze. The conventional way is to use genome browsers to locate and visualize regions of interest.

Detection of epigenetic alterations using tiling arrays.

The epigenetic status of cancer cells is a consequence of the neoplastic transformation of their normal counterpart. Epigenetic changes directly influence gene expression and chromatin organization, which consequently leads to escape from the tumor-suppression mechanisms. Global mapping for specific epigenetic modifications (e.

Sex-biased gene expression in the developing brain: implications for autism spectrum disorders.

Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes.