Chromosomal translocations can result in phenotypic effects of varying severity, depending on the position of the breakpoints and the rearrangement of genes within the interphase nucleus of the ...translocated chromosome regions. Balanced translocations are often asymptomatic phenotypically and are typically detected due to a decrease in fertility resulting from issues during meiosis. Robertsonian translocations are among the most common chromosomal abnormalities, often asymptomatic, and can persist in the population as a normal polymorphism. We serendipitously discovered a Robertsonian translocation between chromosome 21 and chromosome 22, which is inherited across three generations without any phenotypic effect, notably only in females. In situ hybridization with alpha-satellite DNAs revealed the presence of both centromeric sequences in the translocated chromosome. The reciprocal translocation resulted in a partial deletion of the short arm of both chromosomes 21, and 22, with the ribosomal RNA genes remaining present in the middle part of the new metacentric chromosome. The rearrangement did not cause alterations to the long arm. The spread of an asymptomatic heterozygous chromosomal polymorphism in a population can lead to mating between heterozygous individuals, potentially resulting in offspring with a homozygous chromosomal configuration for the anomaly they carry. This new karyotype may not produce phenotypic effects in the individual who presents it. The frequency of karyotypes with chromosomal rearrangements in asymptomatic heterozygous form in human populations is likely underestimated, and molecular karyotype by array Comparative Genomic Hybridization (array-CGH) analysis does not allow for the identification of this type of chromosomal anomaly, making classical cytogenetic analysis the preferred method for obtaining clear results on a karyotype carrying a balanced rearrangement.
Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes ...encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as “SNAREopathies”, including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles’ exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy.
In recent decades, the use of genetic polymorphisms related to specific phenotypes, such as eye color, has greatly contributed to the development of the research field called forensic DNA phenotyping ...(FDP), enabling the investigators of crime cases to reduce the number of suspects, making their work faster and more precise. Eye color is a polygenic phenotype, and many genetic variants have been highlighted, with the major contributor being the HERC2-OCA2 locus, where many single nucleotide variations (SNPs) were identified. Interestingly, the HERC2-OCA2 locus, containing the intronic SNP rs12913832, the major eye color determinant, shows a high level of evolutionary conservation across many species of vertebrates. Currently, there are some genetic panels to predict eye color by genomic DNA analysis, even if the exact role of the SNP variants in the formation of eye color is still poorly understood, with a low level of predictivity in the so-called intermediate eye color. Many variants in OCA2, HERC2, and other genes lie in introns or correspond to synonymous variants, highlighting greater complexity in the mechanism of action of such genes than a simple missense variation. Here, we show the main genes involved in oculocutaneous pigmentation and their structural and functional features, as well as which genetic variants show the highest level of eye color predictivity in currently used FDP assays. Despite the great recent advances and impact of FDP in criminal cases, it is necessary to enhance scientific research to better understand the mechanism of action behind each genetic variant involved in eye color, with the goal of obtaining higher levels of prediction.
PHF21A Related Disorder: Description of a New Case Butera, Ambra; Nicotera, Antonio Gennaro; Di Rosa, Gabriella ...
International journal of molecular sciences,
12/2022, Volume:
23, Issue:
24
Journal Article
Peer reviewed
Open access
(
) gene, located in the short arm of chromosome 11, encodes for BHC80, a component of the Lysine Specific Demethylase 1, Corepressor of REST (LSD1-CoREST) complex. BHC80 is mainly expressed in the ...human fetal brain and skeletal muscle and acts as a modulator of several neuronal genes during embryogenesis. Data from literature relates
variants with Potocki-Shaffer Syndrome (PSS), a contiguous gene deletion disorder caused by the haploinsufficiency of
,
, and
genes. Clinical cardinal features of PSS syndrome are multiple exostoses (due to the
involvement), biparietal foramina (due to the
involvement), intellectual disability, and craniofacial anomalies (due to the
involvement). To date, to the best of our knowledge, a detailed description of
-related disorder clinical phenotype is not described in the literature; in fact, only 14 subjects with microdeletion frameshift or nonsense variants concerning only
gene have been reported. All reported cases did not present
or
variants, and their clinical features did not fit with PSS diagnosis. Herein, by using Exome sequencing, and Sanger sequencing of the region of interest, we describe a case of a child with a paternally inherited (mosaicism of 5%) truncating variant of the
gene (c.649_650del; p.Gln217ValfsTer6), and discuss the new evidence. In conclusion, these patients showed varied clinical expressions, mainly including the presence of intellectual disability, epilepsy, hypotonia, and dysmorphic features. Our study contributes to describing the genotype-phenotype spectrum of patients with PHF21A-related disorder; however, the limited data in the literature have been unable to provide a precise diagnostic protocol for patients with
-related disorder.
During the first wave of COVID-19 infection in Italy, the number of cases and the mortality rates were among the highest compared to the rest of Europe and the world. Several studies demonstrated a ...severe clinical course of COVID-19 associated with old age, comorbidities, and male gender. However, there are cases of virus infection resistance in subjects living in close contact with infected subjects. Thus, to explain the predisposition to virus infection and to COVID-19 disease progression, we must consider, in addition to the genetic variability of the virus and other environmental or comorbidity conditions, the allelic variants of specific human genes, directly or indirectly related to the life cycle of the virus. Here, we analyzed three human genetic polymorphisms belonging to the TMPRSS2 and CCR5 genes in a sample population from Sicily (Italy) to investigate possible correlations with the resistance to viral infection and/or to COVID-19 disease progression as recently described in other human populations. Our results did not show any correlations of the rs35074065, rs12329760, and rs333 polymorphisms with SARS-CoV-2 infection or with COVID-19 disease severity. Further studies on other human genetic polymorphisms should be performed to identify the major human determinants of SARS-CoV-2 viral resistance.
The European anchovy, Engraulis encrasicolus, is currently one of the principal target species for commercial fisheries in Europe. In this study, the mitochondrial Control Region (CR) and the ...Cytochrome Oxidase I (COI) mitochondrial gene were analyzed in 74 specimens of E. encrasicolus from four localities in the central Mediterranean. In both populations, the two markers revealed the presence of two main haplogroups, A and B, already detected in previous investigations of different classes of molecular markers. Both CR and COI markers consistently identified two haplogroups. The COI sequence analysis identified a non-synonymous transversion (T to G) at position 116 of the translated sequence, resulting in an amino acid change. All COI sequences of haplogroup A had an amino acid sequence with alanine in this position, while serine was present in the same position in haplogroup B. The two haplogroups A and B were also discriminated by the variable number of TACA elements at the 5'-end of the mitochondrial CR. The selection tests applied to the COI dataset revealed that codon 116 was not under positive selection, that seven amino acid changes were under purifying selection, and that two amino acids were under episodic positive selection.
Currently, there are no effective therapeutic options for Alzheimer's disease, the most common, multifactorial form of dementia, characterized by anomalous amyloid accumulation in the brain. Growing ...evidence points to neuroinflammation as a major promoter of AD. We have previously shown that the proinflammatory cytokine TNFSF10 fuels AD neuroinflammation, and that its immunoneutralization results in improved cognition in the 3xTg-AD mouse.
Here, we hypothesize that inflammatory hallmarks of AD might parallel with central and peripheral immune response dysfunction. To verify such hypothesis, we used a triple transgenic mouse model of AD. 3xTg-AD mice were treated for 12 months with an anti-TNFSF10 antibody, and thereafter immune/inflammatory markers including COX2, iNOS, IL-1β and TNF-α, CD3, GITR, and FoxP3 (markers of regulatory T cells) were measured in the spleen as well as in the hippocampus.
Spleens displayed accumulation of amyloid-β
(Aβ
), as well as high expression of Treg cell markers FoxP3 and GITR, in parallel with the increased levels of inflammatory markers COX2, iNOS, IL-1β and TNF-α, and blunted IL-10 expression. Moreover, CD3 expression was increased in the hippocampus, consistently with FoxP3 and GITR. After chronic treatment of 3xTg-AD mice with an anti-TNFSF10 antibody, splenic FoxP3, GITR, and the above-mentioned inflammatory markers expression was restored to basal levels, while expression of IL-10 was increased. A similar picture was observed in the hippocampus. Such improvement of peripheral and CNS inflammatory/immune response was associated with decreased microglial activity in terms of TNFα production, as well as decreased expression of both amyloid and phosphorylated tau protein in the hippocampus of treated 3xTg-AD mice. Interestingly, we also reported an increased expression of both CD3 and FoxP3, in sections from human AD brain.
We suggest that neuroinflammation in the brain of 3xTg-AD mice triggered by TNFSF10 might result in a more general overshooting of the immune response. Treatment with an anti-TNFSF10 antibody blunted inflammatory processes both in the spleen and hippocampus. These data confirm the detrimental role of TNFSF10 in neurodegeneration, and corroborate the hypothesis of the anti-TNFSF10 strategy as a potential treatment to improve outcomes in AD.
Different parts of the genome occupy specific compartments of the cell nucleus based on the gene content and the transcriptional activity. An example of this is the altered nuclear positioning of the ...HLXB9 gene in leukaemia cells observed in association with its over-expression. This phenomenon was attributed to the presence of a chromosomal translocation with breakpoint proximal to the HLXB9 gene. Before becoming an interesting gene in cancer biology, HLXB9 was studied as a developmental gene. This homeobox gene is also known as MNX1 (motor neuron and pancreas homeobox 1) and it is relevant for both motor neuronal and pancreatic beta cells development. A spectrum of mutations in this gene are causative of sacral agenesis and more broadly, of what is known as the Currarino Syndrome, a constitutional autosomal dominant disorder. Experimental work on animal models has shown that HLXB9 has an essential role in motor neuronal differentiation. Here we present data to show that, upon treatment with retinoic acid, the HLXB9 gene becomes over-expressed during the early stages of neuronal differentiation and that this corresponds to a reposition of the gene in the nucleus. More precisely, we used the SK-N-BE human neuroblastoma cell line as an in vitro model and we demonstrated a transient transcription of HLXB9 at the 4th and 5th days of differentiation that corresponded to the presence, predominantly in the cell nuclei, of the encoded protein HB9. The nuclear positioning of the HLXB9 gene was monitored at different stages: a peripheral location was noted in the proliferating cells whereas a more internal position was noted during differentiation, that is while HLXB9 was transcriptionally active. Our findings suggest that HLXB9 can be considered a marker of early neuronal differentiation, possibly involving chromatin remodeling pathways.
Abstract Mammalian chitinases consisting of CHIA, CHIT1, CHI3L1, CHI3L2 and CHID1 exert important biological roles in the monocyte lineage and chronic inflammatory diseases. Pathological bone ...resorption is a cause of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, osteoporosis, periodontitis and cancer metastasis. The biologic role of chitinases in bone resorption is poorly understood. In this study, we evaluated the expression of the chitinases family during osteoclast differentiation. The expression of CHIA, CHI3L2 and CHID1 resulted unchanged during osteoclast differentiation, whereas CHIT1 and CHI3L1 increased significantly. We also observed that CHIT1 and CHI3L1 are involved in osteoclast function. Indeed, silencing CHIT1 and CHI3L1 with siRNA resulted in a significant decrease in bone resorption activity. In addition, transfection with CHIT1 or CHI3L1 siRNA and co-transfection with both decreased the levels of the pro-differentiative marker MMP9. Overall, these discoveries reveal a novel and crucial role for both CHIT1 and CHI3L1 in promoting bone resorption and identifying new potential candidate markers for therapeutic targeting.
Combined treatments which use nanoparticles and drugs could be a synergistic strategy for the treatment of a variety of cancers to overcome drug resistance, low efficacy, and high-dose-induced ...systemic toxicity. In this study, the effects on human colon adenocarcinoma cells of surface modified Fe3O4 magnetic nanoparticles (MNPs) in combination with sodium butyrate (NaBu), added as a free formulation, were examined demonstrating that the co-delivery produced a cytotoxic effect on malignant cells. Two different MNP coatings were investigated: a simple polyethylene glycol (PEG) layer and a mixed folic acid (FA) and PEG layer. Our results demonstrated that MNPs with FA (FA-PEG@MNPs) have a better cellular uptake than the ones without FA (PEG@MNPs), probably due to the presence of folate that acts as an activator of folate receptors (FRs) expression. However, in the presence of NaBu, the difference between the two types of MNPs was reduced. These similar behaviors for both MNPs likely occurred because of the differentiation induced by butyrate that increases the uptake of ferromagnetic nanoparticles. Moreover, we observed a strong decrease of cell viability in a NaBu dose-dependent manner. Taking into account these results, the cooperation of multifunctional MNPs with NaBu, taking into consideration the particular cancer-cell properties, can be a valuable tool for future cancer treatment.
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