Role In Down Syndrome Research Articles

The role of Down syndrome cell adhesion molecule in Down syndrome.

Down syndrome (DS) is caused by the presence of an extra copy of the entire or a portion of human chromosome 21 (HSA21). This genomic alteration leads to elevated expression of numerous HSA21 genes, resulting in a variety of health issues in individuals with DS. Among the genes located in the DS "critical region" of HSA21, Down syndrome cell adhesion molecule (DSCAM) plays an important role in neuronal development. There is a growing body of evidence underscoring DSCAM's involvement in various DS-related disorders. This review aims to provide a concise overview ofthe established functions of DSCAM, with a particular focus on its implications in DS. We delve into the roles that DSCAM plays in DS-associated diseases. In the concluding section ofthis review, we explore prospective avenues for future research to further unravel DSCAM's role in DS and opportunities for therapeutic treatments.

The Features of Down Syndrome and the Risk of Parent’s Age

Background: Down syndrome is the most common autosomal disorder in humans. And the most common genetic chromosomal disorder causing mental disability in children.
 It also cause other medical abnormalities including heart and gastrointestinal disorder.
 These children sharing common features and characteristic faces.
 Each individual with this syndrome will not have all the features, but they will have a unique combination.
 Objective: In our study we try to spot light on the craniofacial features of Down syndrome in our country: their percentage; to compare it with another study in other countries.
 We also focus on the craniofacial features accuracy in diagnosis. Karyotyping not always available.
 Also we study the risk factors where we found that the mother age is not the only risk factor, but also the father age play a big role in Down syndrome and this risk factor needs to be studied with large number of patients.
 Also we study the problems associated with Down syndrome and its percentages, and to compare it with other study done in our neighbor's countries, where we found many differences
 Setting and Design: Our study is a descriptive, case series retrospective study was conducted in Benghazi Libya's children hospital.
 This study includes 73 patients who were referred to our Genetic clinic from October 2016 to march 2017.
 The genetic clinic is the only clinic in Benghazi and the whole East of Libya.
 This clinic follows children with DS and children with dysmorphic features in Benghazi and the Libyan ‘east.
 Materials and Methods: We studied 73 children randomly from different age group, and different socioeconomic classes, who attend the genetic clinic, which is an outpatient clinic and the only clinic which follows children with DS and dysmorphic feature in a pediatric hospital in Benghazi- Libya.
 We took the history from the parent (the father and the Mother).
 The investigation done in our hospital.
 Father and mother age at pregnancy.
 Spontaneous or induced pregnancy.
 Drug history of the mothers and fathers.
 History of abortion and normal children.
 Any other baby with Down syndrome or other dysmorphic features.
 Echocardiography done for all children.
 Ultrasound abdomen and brain did for all children.
 Thyroid function test done for all children and repeated annually for all children.
 The diagnosis done mainly by clinical features. Some cases (40 cases) are proved by karyotype chromosomal analysis.

Neurodevelopmental disorders: 2022 update.

With a prevalence of 2-4% of the worldwide population, neurodevelopmental disorders (NDDs) comprise a heterogeneous group of disorders associated with neurodevelopmental dysfunction, including intellectual disability (ID), autism spectrum disorder (ASD), Down syndrome (DS) and attention-deficit/hyperactivity disorder (ADHD) among others. However, due to their heterogeneity and overlapping clinical features, NDDs such as ASD are often misdiagnosed, while for others with more distinct symptoms, such as Rett syndrome or DS, the mechanisms underlying their pathogenesis remain elusive. Last year, important steps in the mechanistic understanding of several NDDs have been achieved. New preclinical models demonstrated causality between PAK3 mutations and disorders associated with social deficiencies. ARID1B mutations have been linked to neuroectoderm specification in Coffin-Siris syndrome and DNA damage was established as an important pathologic mechanism in Aicardi-Goutières syndrome. Moreover, alterations in basic molecular processes including translation and histone acetylation have been established as major traits in the pathology of X-linked ID and Rett syndrome, revealing new pathogenetic mechanisms. Last year, advances in bioinformatics have begun to shed light on the human repeatome, a largely unexplored part of our genome, and how alterations in these sequences have a central role in ASD. The role of mitochondria in neuropathology was clarified last year with the discovery of previously unknown vesicles derived from mitochondria with a putative role in DS. An interesting discovery in the field of basic neurodevelopment showed that during postnatal brain development, changes in genome architecture and transcriptional dynamics progress independently of sensory experience. Finally, our neurocentric views of NDDs are changing as new players such as astrocytes are revealed to be crucial in neuropathology. The role of astrocytes has been clarified for some pathologies such as ASD and DS, linking well-known genetic mutations to impaired astrocyte function.

The Study of Alternative Splicing Events in Human Induced Pluripotent Stem Cells From a Down's Syndrome Patient.

Down's syndrome (DS) is one of the most commonly known disorders with multiple congenital disabilities. Besides severe cognitive impairment and intellectual disability, individuals with DS also exhibit additional phenotypes of variable penetrance and severity, with one or more comorbid conditions, including Alzheimer's disease, congenital heart disease, or leukemia. Various vital genes and regulatory networks had been studied to reveal the pathogenesis of the disease. Nevertheless, very few studies have examined alternative splicing. Alternative splicing (AS) is a regulatory mechanism of gene expression when making one multi-exon protein-coding gene produce more than one unique mature mRNA. We employed the GeneChip Human Transcriptome Array 2.0 (HTA 2.0) for the global gene analysis with hiPSCs from DS and healthy individuals. Examining differentially expressed genes (DEGs) in these groups and focusing on specific transcripts with AS, 466 up-regulated and 722 down-regulated genes with AS events were identified. These genes were significantly enriched in biological processes, such as cell adhesion, cardiac muscle contraction, and immune response, through gene ontology (GO) analysis of DEGs. Candidate genes, such as FN1 were further explored for potentially playing a key role in DS. This study provides important insights into the potential role that AS plays in DS.

Peripheral Oxidation Markers in Down Syndrome Patients: The Better and the Worse.

Oxidative stress plays an important role in Down syndrome (DS) pathology since the gene dose effect leads to abnormal levels of certain enzymes and metabolites. In this review, we focused on relatively easy-to-obtain, peripheral markers of oxidative stress and inflammation, in order to compare the levels of these markers in DS patients and chromosomally healthy persons. Studies taking into account age- and sex-matched control groups were of particular interest in this context. We analyzed the factors that influence the levels of said markers in both groups (i.e., the usefulness of the markers), including the age of DS patients, occurrence of regular trisomy 21 or mosaicism, physical activity of patients, and the onset of Alzheimer's disease in DS. This paper was conceived as a handbook—to help for selecting suitable, easy-to-obtain markers for monitoring of the health status of DS patients (e.g., in nutritional studies and during dietary supplementation).

RCAN1 and its Role in Down Syndrome via its Regulation of Calcineurin

RCAN1 and its Role in Down Syndrome via its Regulation of Calcineurin

Folate System Gene Variant rs1801394 66A>G may have a Causal Role in Down Syndrome in the Eastern Indian Population.

Down syndrome (DS) is associated with trisomy of the 21st chromosome in more than 95% cases. The extra chromosome mostly derives due to abnormal chromosomal segregation, i.e. non-disjunction, during meiosis. Earlier reports showed that abnormal folate metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation. We analyzed three functional folate gene variants, namely 5-methyltetrahydrofolate-homocysteine methyltransferase rs1805087, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase rs1801394, and reduced folate carrier 1 rs1051266, for contribution in the etiology of DS. Ethnically matched subjects including DS probands (N=183), their parents (N=273), and controls (N=286) were recruited after obtaining informed written consent for participation. Karyotype analysis confirmed trisomy 21 in DS patients recruited. Genomic DNA, purified from peripheral blood leukocytes was used for genotyping of the target sites by PCR based methods, and data obtained was subjected to population- as well as family-based association analysis. Frequency of rs1801394 ‘G’ allele and ‘GG’ genotype was higher in DS probands (P < 0.0001). Statistically significant higher occurrence of the ‘G’ allele in parents of DS probands (P < 0.0001) and maternal bias in transmission of the “G” allele was also noticed (P < 0.0001). Genetic model analysis demonstrated rs1801394 “G” as a risk allele under both dominant and recessive models. DS probands also showed higher occurrence of rs1051266 “G” (P = 0.05). Quantitative trait analysis revealed significant negative influence of rs1805087 “A” on birth weight. Screening for rs1801394 “G” could be useful in monitoring the risk of DS, at least in the studied population.

Can EGCG Alleviate Symptoms of Down Syndrome by Altering Proteolytic Activity?

Down syndrome (DS), also known as “trisomy 21”, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. Silencing these extra genes is beyond existing technology and seems to be impractical. A number of pharmacologic options have been proposed to change the quality of life and lifespan of individuals with DS. It was reported that treatment with epigallocatechin gallate (EGCG) improves cognitive performance in animal models and in humans, suggesting that EGCG may alleviate symptoms of DS. Traditionally, EGCG has been associated with the ability to reduce dual specificity tyrosine phosphorylation regulated kinase 1A activity, which is overexpressed in trisomy 21. Based on the data available in the literature, we propose an additional way in which EGCG might affect trisomy 21—namely by modifying the proteolytic activity of the enzymes involved. It is known that, in Down syndrome, the nerve growth factor (NGF) metabolic pathway is altered: first by downregulating tissue plasminogen activator (tPA) that activates plasminogen to plasmin, an enzyme converting proNGF to mature NGF; secondly, overexpression of metalloproteinase 9 (MMP-9) further degrades NGF, lowering the amount of mature NGF. EGCG inhibits MMP-9, thus protecting NGF. Urokinase (uPA) and tPA are activators of plasminogen, and uPA is inhibited by EGCG, but regardless of their structural similarity tPA is not inhibited. In this review, we describe mechanisms of proteolytic enzymes (MMP-9 and plasminogen activation system), their role in Down syndrome, their inhibition by EGCG, possible degradation of this polyphenol and the ability of EGCG and its degradation products to cross the blood–brain barrier. We conclude that known data accumulated so far provide promising evidence of MMP-9 inhibition by EGCG in the brain, which could slow down the abnormal degradation of NGF.

Dysfunctions of mitochondria in close association with strong perturbation of long noncoding RNAs expression in down syndrome.

Trisomy 21 is the most common chromosomal disorder and underlies Down syndrome. Epigenetics, such as DNA methylation and post-translational histone modifications, plays a vital role in Down syndrome. However, the functions of epigenetics-related long noncoding RNAs (lncRNAs), found to have an impact on neural diseases such as Alzheimer's disease, remain unknown in Down syndrome. In this study, we analyzed the RNA sequencing data from Down syndrome-induced pluripotent stem cells (iPSCs) and normal iPSCs. A large number of lncRNAs were identified differentially expressed in Down syndrome-iPSCs. Notably, stronger perturbation was shown in the expression of lncRNAs compared to protein coding genes (Kolmogorov-Smirnov test, P<0.05), suggesting that lncRNAs play more important roles in Down syndrome. Through gene set enrichment analysis and bi-clustering, we also found that most of the differential expressed lncRNAs were closely associated with mitochondrial functions (e.g. mitochondrion organization, P=3.21×10-17; mitochondrial ATP synthesis coupled electron transport, P=1.73×10-19 and mitochondrial membrane organization, P=4.04×10-8). PCR-array and qRT-PCR results revealed that almost all genes related to mitochondria were down-regulated in Down syndrome-iPSCs, implying that mitochondria were dysfunctional in Down syndrome (e.g. ATP5B, Fold Change=-8.2317; COX6A1, Fold Change=-12.7788 and SLC25A17, Fold Change=-22.1296). All in all, our study indicated that a stronger perturbation of lncRNAs expression may lead to the dysfunction of mitochondria in Down syndrome.

The contribution of the citrate pathway to oxidative stress in Down syndrome.

Inflammatory conditions and oxidative stress have a crucial role in Down syndrome (DS). Emerging studies have also reported an altered lipid profile in the early stages of DS. Our previous works demonstrate that citrate pathway activation is required for oxygen radical production during inflammation. Here, we find up-regulation of the citrate pathway and down-regulation of carnitine/acylcarnitine carrier and carnitine palmitoyl-transferase 1 genes in cells from children with DS. Interestingly, when the citrate pathway is inhibited, we observe a reduction in oxygen radicals as well as in lipid peroxidation levels. Our preliminary findings provide evidence for a citrate pathway dysregulation, which could be related to some phenotypic traits of people with DS.

Explorative Investigation on Thyroid Peroxidase and Sodium Iodide Symporter Gene Variants in Down Syndrome

Objective: Down syndrome (DS), the most common cause of intellectual disability, is frequently associated with thyroid malfunction. Normal thyroid function is essential for growth, neuronal development as well as cognition. Sodium iodide symporter (NIS) and thyroid peroxidase (TPO) are important enzymes for thyroid and to understand their role in DS, we investigated variants in these two genes in families with DS probands (N=183) and controls (N=222).Methods: Genomic DNA isolated from peripheral blood was analyzed by sequencing for genotyping of target sites. Data obtained was analyzed by population- and family-based statistical methods. SNP-SNP interactions were analyzed by Multifactor dimensionality reduction (MDR) test.Results: Out of twelve, only two (rs4808708 and rs4808709) functional SNPs in NIS and among eleven only one SNP, rs1126799 in TPO were polymorphic. Case-control analysis failed to show any statistically significant difference. Family-based analysis revealed significant over transmission of rs1126799 ‘C’ allele to probands. MDR analysis showed synergistic effect of rs1126799 with both rs4808708 and rs4808709. rs4808708 and rs4808709 showed redundancy amongst themselves.Conclusion: This pioneering association study on TPO and NIS gene variants in DS subjects showed synergistic interaction between the SNPs, in absence of any independent contribution, and together may regulate thyroid hormone metabolism.

Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: possible role in Down syndrome.

Individuals with Down syndrome (DS) present important motor deficits that derive from altered motor development of infants and young children. DYRK1A, a candidate gene for DS abnormalities has been implicated in motor function due to its expression in motor nuclei in the adult brain, and its overexpression in DS mouse models leads to hyperactivity and altered motor learning. However, its precise role in the adult motor system, or its possible involvement in postnatal locomotor development has not yet been clarified. During the postnatal period we observed time-specific expression of Dyrk1A in discrete subsets of brainstem nuclei and spinal cord motor neurons. Interestingly, we describe for the first time the presence of Dyrk1A in the presynaptic terminal of the neuromuscular junctions and its axonal transport from the facial nucleus, suggesting a function for Dyrk1A in these structures. Relevant to DS, Dyrk1A overexpression in transgenic mice (TgDyrk1A) produces motor developmental alterations possibly contributing to DS motor phenotypes and modifies the numbers of motor cholinergic neurons, suggesting that the kinase may have a role in the development of the brainstem and spinal cord motor system.

A novel binding protein of single-minded 2: the mitotic arrest-deficient protein MAD2B

Single-minded 2 (Sim2) gene, located at the Down syndrome (DS) critical region, is thought to be particularly important because of its critical role in the development of the central nervous system (CNS) and its overexpression resulting in impairment of learning and memory which is similar to that in DS. However, its exact role in DS still remains elusive. Using a yeast two-hybrid interaction trap, we identified the mitotic arrest-deficient protein MAD2B as a novel Sim2 binding protein. Through confocal laser scanning microscopy, we found that Sim2 and MAD2B colocalized in rat cortex neurons. This interaction between Sim2 and MAD2B was also confirmed by co-immunoprecipitation. Moreover, levels of mRNA and protein of both Sim2 and MAD2B were regulated during nervous development as detected by quantitative RT-PCR and western blot analysis. We also found that overexpression of Sim2 affected the distribution of MAD2B in primary culture neurons. The results of confocal laser scanning microscopy and co-immunoprecipitation indicated that in neurons, MAD2B interacted with clathrin light chain A, which is best known for its role in endocytosis. In addition, it was found that overexpression of Sim2 or MAD2B caused deficits in clathrin-mediated endocytosis. Furthermore, overexpression of both MAD2B and Sim2 exacerbates their own inhibitory effect on transferrin uptake. These results suggest that MAD2B may mediate Sim2 function during development in CNS and thereby play a critical role in pathophysiological mechanisms in DS.

Functional genetic polymorphisms in SIM2 and ETS2: Role in Down syndrome

International Journal of Developmental NeuroscienceVolume 30, Issue 8 p. 655-655 Abstract Functional genetic polymorphisms in SIM2 and ETS2: Role in Down syndrome First published: 30 March 2012 https://doi.org/10.1016/j.ijdevneu.2012.03.275AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume30, Issue8Abstracts to the 19th Biennial Meeting of the International Society for Developmental Neuroscience, 11-14 January 2012, Mumbai, IndiaDecember 2012Pages 655-655 RelatedInformation

Prolonged coenzyme Q10 treatment in Down syndrome patients, effect on DNA oxidation

Oxidative stress is known to play a relevant role in Down syndrome (DS) and its effects are documented from embryonic life. Oxidative DNA damage has been shown to be significantly elevated in Down syndrome patients, and this has been indicated as an early event promoting neurodegeneration and Alzheimer type dementia. The aim of this study was to investigate the efficacy of coenzyme Q10 (CoQ10) in delaying the effect of oxidative damage in these patients. In our previous study we demonstrated a mild protective effect of CoQ10 on DNA, although the treatment was unable to modify the overall extent of oxidative damage at the patient level. Possible limitations of the previous study were: time of treatment (6 months) or spectrum of DNA lesions detected. In order to overcome these limitations we planned a continuation of the trial aimed at evaluating the effects of CoQ10 following a prolonged treatment. Our results highlight an age-specific reduction in the percentage of cells showing the highest amount of oxidized bases, indicating a potential role of CoQ10 in modulating DNA repair mechanisms.

Exploratory investigation on functional significance of ETS2 and SIM2 genes in Down syndrome.

Trisomy of the 21st chromosome leads to an over dosage of several regulatory genes in Down syndrome (DS). Though allelic and genotypic combinations formed between genes are interesting, till date, this particular area has never been explored in DS. In the present investigation four SNPs in two transcription factors, Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2), located in the 21st chromosome were genotyped to understand their role in DS. Genomic DNA of eastern Indian probands with DS (N = 132), their parents (N = 209) and ethnically matched controls (N = 149) was subjected to PCR-based analyses of functionally important SNPs followed by statistical analyses. ETS2 rs461155 showed high heterozygosity in DS. Significantly lower frequency of SIM2 C-G haplotype (rs2073601-rs2073416) was noticed in individuals with DS (P value = 0.01669) and their fathers (P value = 0.01185). Significantly lower frequency of the A-C-C-G with higher frequency of A-C-A-G haplotypes was also noticed in subjects with DS (P value = 0.02089 and 0.00588 respectively). Data obtained indicate that the rs2073601 ‘A’ allele, responsible for nonsynonymous substitution of leucine to methionine, may have some role in DS in this population.

Exploratory Investigation on Functional Significance ofETS2andSIM2Genes in Down Syndrome

Trisomy of the 21st chromosome leads to an over dosage of several regulatory genes in Down syndrome (DS). Though allelic and genotypic combinations formed between genes are interesting, till date, this particular area has never been explored in DS. In the present investigation four SNPs in two transcription factors, Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2), located in the 21st chromosome were genotyped to understand their role in DS. Genomic DNA of eastern Indian probands with DS (N= 132), their parents (N= 209) and ethnically matched controls (N= 149) was subjected to PCR-based analyses of functionally important SNPs followed by statistical analyses.ETS2rs461155 showed high heterozygosity in DS. Significantly lower frequency ofSIM2C-G haplotype (rs2073601-rs2073416) was noticed in individuals with DS (Pvalue = 0.01669) and their fathers (Pvalue = 0.01185). Significantly lower frequency of the A-C-C-G with higher frequency of A-C-A-G haplotypes was also noticed in subjects with DS (Pvalue = 0.02089 and 0.00588 respectively). Data obtained indicate that the rs2073601 ‘A’ allele, responsible for nonsynonymous substitution of leucine to methionine, may have some role in DS in this population.

Clinical manifestations of the deletion of Down syndrome critical region including DYRK1A and KCNJ6

A relatively small region of human chromosome 21 (Hsa21) is considered to play a major role in Down syndrome (DS) phenotypes, and the concept of a Down syndrome critical region (DSCR) has been proposed. The goal of the phenotype-genotype correlation study is to discover which genes are responsible for each DS phenotype. Loss of the genomic copy numbers of Hsa21 can give us important suggestion to understand the functions of the involved genes. Genomic copy number aberrations were analyzed by micro-array-based comparative genomic hybridization (aCGH) in 300 patients with developmental delay. Partial deletions of Hsa21 were identified in three patients with developmental delay, epilepsy, microcephaly, and distinctive manifestations. Two of the patients had mosaic deletions of 21q22-qter including a part of DSCR; one of whom whose mosaic ratio was higher than the other showed more severe brain morphogenic abnormality with colpocephaly, which was similar to the previously reported patients having pure deletions of 21q22-qter, indicating the critical region for cortical dysplasia at this region. The remaining patient had the smallest microdeletion with 480 kb in DSCR including DYRK1A and KCNJ6. Although we could not identify any nucleotide alteration in DYRK1A and KCNJ6 in our cohort study for 150 patients with mental retardation with/without epilepsy, this study underscores the clinical importance of DSCR not only for DS but also for developmental disorders.

DNA Study Gets a Snip Closer to Understanding Personality

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessDNA Study Gets a Snip Closer to Understanding PersonalityJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:6 Aug 2010https://doi.org/10.1176/pn.45.15.psychnews_45_15_024AbstractSome 4,000 individuals living on the Mediterranean island of Sardinia have a special claim to fame in the world of psychiatric genetics.They are a genetically homogenous population and thus ideal for gene hunts. They also agreed to participate in what appears to be the first genomewide association study to identify genes undergirding the major personality traits of neuroticism, extraversion, openness, agreeableness, and conscientiousness identified by the Revised NEO Personality Inventory, and they were willing to provide blood samples for DNA analysis.This vigorous older man who lives on Sardinia is one of the many individuals on the island who agreed to participate in the study looking for genes underpinning the five big personality traits.Credit: Antonio Terracciano, Ph.D., et al.The researchers were headed by Antonio Terracciano, Ph.D., a staff scientist at the U.S. National Institute on Aging. They looked to see whether they could find genomewide significant associations between some of the snips of genetic material taken from subjects' DNA and the personality dimensions of interest. Unfortunately they could not, they reported in the June Molecular Psychiatry. Nonetheless, they did identify a handful of snips that might contribute to these traits.For example, a snip from chromosome 20 called SNAP25 was linked with neuroticism. SNAP25 had already been linked with mood disorders, attention-deficit/hyperactivity disorder, and schizophrenia.A snip located close to the gene that codes for brain-derived neurotrophic factor was associated with extraversion. This was the most surprising finding, Terracciano told Psychiatric News, because they had expected it to be linked with neuroticism, not extraversion, as some previous studies had found. Nonetheless, “the finding has been corroborated in other samples,” he said.The strongest link was found between a snip called rs644148 and the personality trait of openness. This snip was linked to extraversion as well. This snip is not from any known gene, and its function is unknown.Several snips of genetic material located within or close to the CLOCK gene were linked with the personality trait of agreeableness. This was perhaps the most interesting finding, Terracciano and his group indicated, because the CLOCK gene is known to influence circadian rhythms and has been coupled with sleep and mood disorders.As for the personality trait of conscientiousness, it was associated with snips located within a gene on chromosome 21 called the DYRK1A gene. This gene is also known to be overly expressed in the brains of subjects with Down syndrome and to influence beta-amyloid production in the brains of patients with Alzheimer's. However, the reason why a conscientiousness-related gene might play a role in Down syndrome or Alzheimer's is far from clear, the researchers acknowledged.“Our findings and those of other genome-wide association studies are unlikely to have immediately translational impact,” Terracciano told Psychiatric News, “but they suggest a role of specific and often novel genetic variants in complex traits and diseases. These common genetic variants are [also] useful in pointing to biological pathways or genes that might harbor rarer variants with larger effects in a few families. It is also conceivable that they could be points of intervention by modifications in environmental factors or eventually in pharmaceutical products; but this is a distant prospect.”The study was funded by the National Institutes of Health and NARSAD.An abstract of “Genome-Wide Association Scan for Five Major Dimensions of Personality” is posted at <www.nature.com/mp/journal/v15/n6/abs/mp2008113a.html>. ISSUES NewArchived

Neonatal Mice of the Down Syndrome Model, Ts65Dn, Exhibit Upregulated VIP Measures and Reduced Responsiveness of Cortical Astrocytes to VIP Stimulation

The Ts65Dn segmental mouse model of Down syndrome (DS) possesses a triplication of the section of chromosome 16 that is most homologous to the human chromosome 21 that is trisomic in DS. This model exhibits many of the characteristics of DS including small size, developmental delays, and a decline of cholinergic systems and cognitive function with age. Recent studies have shown that vasoactive intestinal peptide (VIP) systems are upregulated in aged Ts65Dn mice and that VIP dysregulation during embryogenesis is followed by the hypotonia and developmental delays as seen in both DS and in Ts65Dn mice. Additionally, astrocytes from aged Ts65Dn brains do not respond to VIP stimulation to release survival-promoting substances. To determine if VIP dysregulation is age-related in Ts65Dn mice, the current study examined VIP and VIP receptors (VPAC-1 and VPAC-2) in postnatal day 8 Ts65Dn mice. VIP and VPAC-1 expression was significantly increased in the brains of trisomic mice compared with wild-type mice. VIP-binding sites were also significantly increased in several brain areas of young Ts65Dn mice, especially in the cortex, caudate/putamen, and hippocampus. Further, in vitro treatment of normal neurons with conditioned medium from VIP-stimulated Ts65Dn astrocytes from neonatal mice did not enhance neuronal survival. This study indicates that VIP anomalies are present in neonatal Ts65Dn mice, a defect occurs in the signal transduction mechanism of the VPAC-1 VIP receptor, cortical astrocytes from neonatal brains are dysfunctional, and further, that VIP dysregulation may play a significant role in DS.