Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212096 | GEO | 2022/10/28
REPOSITORIES: GEO
Similar Datasets
Project description:We developed human induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n=7) and their unaffected siblings (n=6).
2020-05-13 | GSE150429 | GEO
Project description:Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Phenotypic differences have been reported between PMS participants carrying small "class I" mutations and large "class II" mutations; however, the molecular perturbations underlying these divergent phenotypes remain obscure. Using peripheral blood transcriptome and serum metabolome profiling, we examined the molecular perturbations in the peripheral circulation associated with a full spectrum of PMS genotypes spanning class I (n = 37) and class II mutations (n = 39). Transcriptomic data revealed 52 genes with blood expression profiles that tightly scale with 22q.13.3 deletion size. Furthermore, we uncover 208 underexpressed genes in PMS participants with class II mutations, which were unchanged in class I mutations. These genes were not linked to 22q13.3 and were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions, and cytotoxic natural killer (NK) immune cell signatures. In silico predictions estimated a reduction in CD56+ CD16- NK cell proportions in class II mutations, which was validated by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered in PMS participants with class II mutations and confirmed a general reduction in sphingolipid metabolism. Collectively, these results provide new evidence linking PMS participants carrying class II mutations with decreased expression of cytotoxic cell signatures, reduced relative proportions of NK cells, and lower sphingolipid metabolism. These findings highlight alternative avenues for therapeutic development and offer new mechanistic insights supporting genotype-to-phenotype associations in PMS.
| S-EPMC9579712 | biostudies-literature
Project description:<p>Progressive multiple sclerosis (PMS) is currently diagnosed retrospectively. Here, we work towards a set of biomarkers that could assist in early diagnosis of PMS. A selection of cerebrospinal fluid metabolites (n=15) was shown to differentiate between PMS and its preceding phenotype in an independent cohort (AUC=0.93). Complementing the classifier with conformal prediction showed that highly confident predictions could be made, and that three out of eight patients developing PMS within three years of sample collection were predicted as PMS at that time point. Finally, this methodology was applied to PMS patients part of a clinical trial for intrathecal treatment with rituximab. The methodology showed that 68% of the patients decreased their similarity to the PMS phenotype one year after treatment. In conclusion, the inclusion of confidence predictors contributes with more information compared to traditional machine learning, and this information is relevant for disease monitoring.</p><p><br></p><p><strong>Cohort 1 assays</strong> are reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS1464' rel='noopener noreferrer' target='_blank'><strong>MTBLS1464</strong></a>.</p><p><strong>Cohort 2 assays</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS558' rel='noopener noreferrer' target='_blank'><strong>MTBLS558</strong></a>.</p>
2023-05-31 | MTBLS1464 | MetaboLights
Project description:Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome
| PRJNA873951 | ENA
Project description:We performed mRNA transcriptional profiling on 99 hemizygotic lines (Df/+) from the DrosDel project covering 68% of chromosome 2L, in order to understand how changes in gene copy number affect overall transcriptome.
2016-01-31 | GSE61509 | GEO
Project description:The aim of the study is to identify genetic mechanisms of longevity and to characterize their interaction with the environment. Using the results the future health of people without familial longevity can be improved in old age. Long-lived siblings of European descent were recruited together with their offspring and the partners of the offspring. Families were recruited if at least two long-lived siblings were alive and fulfilled the age criterion of 89 years or older for males and 91 years or older for females, representing less than 0.5% of the Dutch population in 2001.
2019-07-11 | MTBLS974 | MetaboLights
Project description:Shank3 is a postsynaptic protein that complexes with group 1 metabotropic, AMPA-, and NMDA-type glutamate receptors. Mutations of Shank3 are causal for Phelan-McDermid syndrome (PMS) and associated autism phenotypes. Individuals with PMS often exhibit sensitivity to novelty or stress that can result in behavioral deterioration. Here we use a Shank3 mouse model with face-validity to PMS [Shank(3∆C/+)] and perform a transcriptomic analysis of principal neurons from neocortex of mice subjected to brief swim stress. Analysis reveals overrepresented pathways related to synapses accompanied by elevated expression of the immediate early gene Homer1a. In normal brain Homer1a is dynamically expressed in association with motivated behavior and mediates an essential step in sleep-related homeostatic down-scaling of synaptic proteins. This is consistent with observations that synaptic Shank3 expression requires Homer cross-linking, which is interrupted by Homer1a. Accentuated Homer 1a expression in Shank3(∆C/+) results in marked reductions of Shank3 expression, changes in synapse composition and NMDA-dependent synaptic plasticity, and disruption of social motivation. Deletion of Homer1a partially mitigates stress-induced phenotypes in Shank3(∆C/+) mice. Homer 1a is required for developmental plasticity, learning and memory, yet its enhanced expression in Shank3(∆C/+) may underlie a vulnerability of PMS patients that highlights the challenge of clinical management.
2021-11-18 | GSE174111 | GEO
Project description:To investigate the effect of YTHDF1 on LPS-induced inflammation, we performed RNA-seq with the total RNA extracted from peritoneal macrophages (PMs) with or without YTHDF1 deletion. Ythdf1-/- or wild type mice were intraperitoneally injected with 6% starch broth. Three days later, PMs were isolated and cultured overnight. Then, the PMs were treated by LPS (1 μg/mL) or PBS for 6 hours, followed by RNA extraction and RNA-seq.
2023-08-08 | GSE238236 | GEO
Project description:We have previously reported on two brothers, PM and SM, that carry identical compound heterozygous PRKN mutations but show significantly different clinical Parkinson disease (PD) phenotypes. The occurrence of juvenile cases demonstrates that PD is not necessarily an age-associated disease; indeed, evidence is accumulating that there is a developmental component to PD pathogenesis. The divergence in the clinical presentations between PM and SM lead us to hypothesize that an additional genetic modifier(s) may influence the risk conferred by PRKN. To test our hypothesis, we differentiated human induced pluripotent stem cells (iPSCs) from SM and PM into mitotically active mesencephalic neural precursor cells (floor plate cells) and early postmitotic dopaminergic neurons, and performed whole exome sequencing, and transcriptomic and metabolomics analysis. Our transcriptomic analysis revealed a significant down regulation of three known neurodevelopmentally relevant cell adhesion molecules in PM compared to SM cultures on days 11 and 25 of differentiation, CNTN4, CNTN6, and CHL1. In addition, several HLA genes, known to play a role in neurodevelopment, independent of their well-established function in immunity, were differentially regulated in developing dopamine neurons. EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further report on a single nucleotide polymorphism in DBH, a gene encoding an enzyme involved in dopamine metabolism, as well as differential expression. Our metabolomics data reveal differential biosynthesis of tyrosine, the precursor for dopamine synthesis. Lastly, our whole exome sequencing revealed the homozygous deletion in SM of two glutathione S-transferases, GSTM1 and GSTT1, which encode enzymes involved in glutathione (GSH) metabolism. Moreover, our RNA sequencing analysis shows a lack of expression of these two enzymes in SM cells and our metabolomics analysis indicates differences in GSH homeostasis between SM and PM neurons. This finding builds on previous evidence of glutathione dysregulation being implicated in PD pathogenesis. Our data support our hypothesis that additional genetic differences at least partially underlie the differential clinical PD presentation between PM and SM.
2022-04-02 | GSE184694 | GEO
Project description:To investigate the immune function of SEPT2 in the regulation of viral infection, we obtained SEPT2-deficient PMs from SEPT2 conditional knockout mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of wild-type and SEPT2-deficient PMs with VSV or HSV-1 infection.
2022-09-23 | GSE213863 | GEO