oxytocin and Chromosome-Deletion

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS.. Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period.. There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events.. The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results.. Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.

Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 22; Humans; Oxytocin

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by specific social symptoms, restricted interests, stereotyped repetitive behaviors, and delayed language development. The 3q29 microdeletion (3q29del), a recurrent copy number variant, confers a high risk for ASD and schizophrenia, and serves as an important pathological model for investigating the molecular pathogenesis of a large number of neurodevelopmental and psychiatric conditions. Recently, mouse models carrying a deletion of the chromosomal region corresponding to the human 3q29 region (Df/+ mice) were generated and demonstrated neurodevelopmental and psychiatric conditions associated behavioral abnormalities, pointing to the relevance of Df/+ mice as a model for these conditions with high construct and face validity. Currently, the molecular pathogenesis of these behavioral phenotypes in Df/+ mice remains unclear. The oxytocin (OXT) system plays a central role in social behavior across species and has a potential role in ASD. In this study, to elucidate the molecular mechanisms behind impaired social behavior in Df/+ mice, we investigated the possible involvement of OXT signaling in impaired social behavior in Df/+ mice. We demonstrated that OXT administration restored the impaired social behavior in Df/+ mice. We also demonstrated that the number of OXT-positive cells in the paraventricular nucleus (PVN) was significantly lower in Df/+ mice than in wild-type (WT) littermates. Consistent with this, the level of OXT peptide in the cerebral cortex of Df/+ mice was lower than in WT littermates. Our study may provide important insights into the molecular pathophysiological basis of neurodevelopmental and psychiatric conditions, including ASD.

Topics: Animals; Autism Spectrum Disorder; Brain; Chromosome Deletion; Chromosomes, Human, Pair 3; Developmental Disabilities; Disease Models, Animal; Intellectual Disability; Mice; Oxytocin; Social Behavior

Mutations in the synaptic gene

Topics: Animals; Behavior, Animal; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 22; Disease Models, Animal; Hippocampus; Nerve Tissue Proteins; Oxytocin; Prefrontal Cortex; Rats; Social Behavior

CD38 encodes a ligand in the oxytocin signaling pathway. Some single nucleotide polymorphisms in this gene have been associated with low serum oxytocin levels in autism spectrum disorder (ASD) patients. Oxytocin disruption has been hypothesized to account for features of ASD, including impaired communication and social behavior, based on animal studies. Recent human studies have shown administration of oxytocin improving emotion recognition, promoting social behavior, and improving auditory processing of social stimuli in ASD patients. In addition to its role in oxytocin signaling, CD38 is involved in the regulation of calcium concentration in airway smooth muscle with impairment of CD38 being implicated in airway diseases like asthma. While a number of studies have implicated rare chromosomal deletions and duplications in helping determine genetic risk for autism, there are to our knowledge no reports describing rearrangements involving CD38 or deletions in patients with ASD. Here, we present two sisters diagnosed with autism and with features of regression-previously acquired speech lost in the second year of life. The younger sister, who also had asthma, inherited a maternal deletion of 4p15.32 that results in a BST1-CD38 fusion transcript. Their mother's deletion was mosaic and she was not affected. Although further work is required to assess functional consequences of the fusion transcript, we hypothesize that the proband's deletion may have served as a risk factor for autism that, when combined with other susceptibility variants, resulted in a more severe presentation than her sister.

Topics: Adolescent; ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Antigens, CD; Asthma; Child; Child Development Disorders, Pervasive; Chromosome Deletion; Female; Gene Fusion; Genetic Predisposition to Disease; GPI-Linked Proteins; Humans; Longitudinal Studies; Membrane Glycoproteins; Oxytocin; Phenotype; Polymorphism, Single Nucleotide; Signal Transduction; Transcription, Genetic

Retinoids are known to have profound effects on cellular differentiation and embryo pattern formation. In the adult organism, retinoid acid (RA) receptors are present in a large variety of tissues, including brain. However, little is known of the precise roles of RA at these different sites. In the present study we have identified a novel potential target of RA action by identifying an RA response element (RARE) in the human oxytocin (OT) gene promoter. We have used DNA-mediated gene transfer techniques to introduce various portions of the OT 5'-flanking sequences next to the chloramphenicol acetyltransferase (CAT) gene in neuroblastoma cells. RA elicited a marked stimulation of the transcriptional activity of the OT promoter in cells cotransfected with either the human RA receptor alpha, beta, or gamma. In cells cotransfected with the RA receptor alpha, the ED50 of this response was 5 x 10(-10) M. The RA response could also be conferred to a heterologous promoter independent of orientation. 5'-Deletions as well as site-directed mutations demonstrated that four TGACC motifs, located at -162, -156, -103, and -83 in the OT promoter, are necessary for optimal RA induction. Mutation or deletion of any of these elements reduces significantly the RA response. Interestingly, the first two TGACC motifs overlap with the estrogen response element that we have previously characterized in this gene. Furthermore, the TGACC motif located at -83 overlaps with the CCAAT box. We further demonstrate that in neuroblastoma cells transfected with an RAR alpha expression vector expression of the endogenous OT gene is stimulated greater than 4-fold in response to RA. Our studies constitute the first report of a RARE in a neuropeptide gene and define a mechanism by which OT gene expression can be modulated by retinoic acid.

Topics: Animals; Base Sequence; Binding Sites; Carrier Proteins; Cattle; Cell Line; Chloramphenicol O-Acetyltransferase; Chromosome Deletion; Gene Expression; Humans; Hypothalamus; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Mutagenesis, Site-Directed; Oligodeoxyribonucleotides; Oxytocin; Plasmids; Promoter Regions, Genetic; Rats; Receptors, Retinoic Acid; Restriction Mapping; Sequence Homology, Nucleic Acid; Transfection; Tretinoin

Gonadal steroids affect brain function primarily by altering the expression of specific genes, yet the specific mechanisms by which neuronal target genes undergo such regulation are unknown. Recent evidence suggests that the expression of the neuropeptide gene for oxytocin (OT) is modulated by estrogens. We therefore examined the possibility that this regulation occurred via a direct interaction of the estrogen-receptor complex with cis-acting elements flanking the OT gene. DNA-mediated gene transfer experiments were performed using Neuro-2a neuroblastoma cells and chimeric plasmids containing portions of the human OT gene 5'-glanking region linked to the chloramphenicol acetyltransferase gene. We identified a 19-base pair region located at -164 to -146 upstream of the transcription start site which is capable of conferring estrogen responsiveness to the homologous as well as to a heterologous promoter. The hormonal response is strictly dependent on the presence of intracellular estrogen receptors, since estrogen induced stimulation occurred only in Neuro-2a cells co-transfected with an expression vector for the human estrogen receptor. The identified region contains a novel imperfect palindrome (GGTGACCTTGACC) with sequence similarity to other estrogen response elements (EREs). To define cis-acting elements that function in synergism with the ERE, sequences 3' to the ERE were deleted, including the CCAAT box, two additional motifs corresponding to the right half of the ERE palindrome (TGACC), as well as a CTGCTAA heptamer similar to the "elegans box" found in Caenorhabditis elegans. Interestingly, optimal function of the identified ERE was fully independent of these elements and only required a short promoter region (-49 to +36). Our studies define a molecular mechanism by which estrogens can directly modulate OT gene expression. However, only a subset of OT neurons are capable of binding estrogens, therefore, direct action of estrogens on the OT gene may be restricted to a subpopulation of OT neurons.

Topics: Base Sequence; beta-Galactosidase; Cell Line; Chloramphenicol O-Acetyltransferase; Chromosome Deletion; Estradiol; Genes; Humans; Molecular Sequence Data; Mutation; Oxytocin; Plasmids; Promoter Regions, Genetic; Receptors, Estrogen; Restriction Mapping; Transfection