New Insight into the genotype-phenotype correlation of PTH1R variants and primary failure of tooth eruption on an Italian Cohort.

Primary failure of tooth eruption (PFE) is an autosomal dominant disease with penetrance defect. While the clinical phenotype is relatively well-defined since the 70 s of the last centuries, much more need to be clarified about the genetic causes of this condition. In our previous paper we established clinical criteria to better identify PFE patients carrying PTH1R gene variants.

The polyphenolic compound punicalagin protects skin fibroblasts from UVA radiation oxidative damage.

Polyphenols are a class of natural compounds that act as antioxidants, neutralising harmful free radicals that would damage cells and increase the risk of diseases such as cancer, diabetes and heart disease. They also reduce inflammation, which is thought to be at the root of many chronic diseases. We are investigating the photoprotective effects of punicalagin, a type of polyphenolic compound mainly found in pomegranates, against UVA-induced damage in human skin fibroblasts.

Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders.

Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56-200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively.

Remifentanil-induced hyperalgesia in healthy volunteers: a systematic review and meta-analysis of randomized controlled trials.

Recent literature suggests that the withdrawal of remifentanil (RF) infusion can be associated with hyperalgesia in clinical and nonclinical settings. We performed a systematic review and a meta-analysis of randomized controlled trials with cross-over design, to assess the effect of discontinuing RF infusion on pain intensity and areas of hyperalgesia and allodynia in healthy volunteers. Nine studies were included.

Remifentanil does not affect human microglial immune activation in response to pro-inflammatory cytokines.

Remifentanil is a potent ultra-short acting μ-opioid analgesic drug, frequently used in anaesthesia due to its favorable pharmacodynamic and pharmacokinetic profile. It may be associated with the occurrence of hyperalgesia. Preclinical studies suggest a potential role of microglia, although the molecular mechanisms have not been fully elucidated.

Rutin Protects Fibroblasts from UVA Radiation through Stimulation of Nrf2 Pathway.

This study explores the photoprotective effects of rutin, a bioflavonoid found in some vegetables and fruits, against UVA-induced damage in human skin fibroblasts. Our results show that rutin increases cell viability and reduces the high levels of ROS generated by photo-oxidative stress (1 and 2 h of UVA exposure). These effects are related to rutin's ability to modulate the Nrf2 transcriptional pathway.

Gene Variant May Predispose to Familial Asperger Syndrome.

Asperger syndrome (AS) is a pervasive developmental disorder characterized by general impairment in socialization, stereotypical behavior, defective adaptation to the social context usually without intellectual disability, and some high functioning areas related to memory and mathematics. Clinical criteria are not well defined and the etiology is heterogeneous and mostly unknown. Like in typical autism spectrum disorders (ASD), the genetic background plays a crucial role in AS, and often an almost mendelian segregation can be observed in some families.

Mother and Daughter Carrying of the Same Pathogenic Variant in with Discordant Phenotype.

Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.

Mechanisms of the Repeat Instability: How Does the CGG Sequence Expand?

A dynamic mutation in exon 1 of the FMR1 gene causes Fragile X-related Disorders (FXDs), due to the expansion of an unstable CGG repeat sequence. Based on the CGG sequence size, two types of FMR1 alleles are possible: “premutation” (PM, with 56-200 CGGs) and “full mutation” (FM, with >200 triplets). Premutated females are at risk of transmitting a FM allele that, when methylated, epigenetically silences FMR1 and causes Fragile X syndrome (FXS), a very common form of inherited intellectual disability (ID).

Co-Occurrence of Fragile X Syndrome with a Second Genetic Condition: Three Independent Cases of Double Diagnosis.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), --related neurodevelopmental disorder, and 2p25.

Effects of remifentanil on human C20 microglial pro-inflammatory activation.

Objective: Remifentanil (RF) is a potent short-acting μ-opioid receptor agonist. Although preferred for its unique pharmacokinetics, the clinical use may be limited by hyperalgesia. Preclinical studies have shown a potential role of microglia on the development of hyperalgesia, with limited and conflicting evidence on RF.

DNA Methylation, Mechanisms of Inactivation and Therapeutic Perspectives for Fragile X Syndrome.

Among the inherited causes of intellectual disability and autism, Fragile X syndrome (FXS) is the most frequent form, for which there is currently no cure. In most FXS patients, the gene is epigenetically inactivated following the expansion over 200 triplets of a CGG repeat (FM: full mutation). encodes the Fragile X Mental Retardation Protein (FMRP), which binds several mRNAs, mainly in the brain.

The emerging role of the BDNF-TrkB signaling pathway in the modulation of pain perception.

The brain derived neurotrophic factor (BDNF) is a crucial neuromodulator in pain transmission both in peripheral and central nervous system (CNS). Despite evidence of a pro-nociceptive role of BDNF, recent studies have reported contrasting results, including anti-nociceptive and anti-inflammatory activities. Moreover, BDNF polymorphisms can interfere with BDNF role in pain perception.

DNA Methylation in the Diagnosis of Monogenic Diseases.

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA.

Reversion to Normal of Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families.

Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5' UTR of the gene. Full mutation alleles (FM) have more than 200 repeats and result in gene silencing and FXS. FMs arise from maternal premutations (PM) that have 56-200 CGGs; contractions of a maternal PM or FM are rare.

Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene.

Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5' UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers.

Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation.

Fragile X syndrome (FXS) is a very frequent cause of inherited intellectual disability (ID) and autism. Most FXS patients have an expansion over 200 repeats of (CGG) sequence ("full mutation" (FM)) located in the 5'UTR of the FMR1 gene, resulting in local DNA methylation (methylated "full mutation" (MFM)) and epigenetic silencing. The absence of the FMRP protein is responsible for the clinical phenotype of FXS.

The mTOR kinase inhibitor rapamycin enhances the expression and release of pro-inflammatory cytokine interleukin 6 modulating the activation of human microglial cells.

Emerging evidence suggests the potential use of rapamycin in treatment of several neurological disorders. The drug readily crosses the blood brain barrier and may exert direct immunomodulatory effects within the brain. Microglia are the main innate immune cells of the brain, thus critically involved in the initiation and development of inflammatory processes at this level.

CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations.

In fragile X syndrome (FXS), CGG repeat expansion greater than 200 triplets is believed to trigger FMR1 gene silencing and disease etiology. However, FXS siblings have been identified with more than 200 CGGs, termed unmethylated full mutation (UFM) carriers, without gene silencing and disease symptoms. Here, we show that hypomethylation of the FMR1 promoter is maintained in induced pluripotent stem cells (iPSCs) derived from two UFM individuals.

Simpson-Golabi-Behmel syndrome in a female: A case report and an unsolved issue.

Simpson-Golabi-Behmel syndrome is an X-linked recessive overgrowth condition caused by alterations in GPC3 gene, encoding for the cell surface receptor glypican 3, whose clinical manifestations in affected males are well known. Conversely, there is little information regarding affected females, with very few reported cases, and a clinical definition of this phenotype is still lacking. In the present report we describe an additional case, the first to receive a primary molecular diagnosis based on strong clinical suspicion.

Transcriptional Reactivation of the FMR1 Gene. A Possible Approach to the Treatment of the Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG expansion over 200 repeats (full mutation, FM) at the 5' untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene and subsequent DNA methylation of the promoter region, accompanied by additional epigenetic histone modifications that result in a block of transcription and absence of the fragile X mental retardation protein (FMRP). The lack of FMRP, involved in multiple aspects of mRNA metabolism in the brain, is thought to be the direct cause of the FXS phenotype. Restoration of FMR1 transcription and FMRP production can be obtained in vitro by treating FXS lymphoblastoid cell lines with the demethylating agent 5-azadeoxycytidine, demonstrating that DNA methylation is key to FMR1 inactivation.