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Clinical Obesity Apr 2024Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1...
Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.
PubMed: 38596856
DOI: 10.1111/cob.12661 -
MicroRNA (Shariqah, United Arab... Apr 2024Long non-coding RNA (lncRNA) plays a crucial role in various biolog-ical processes, and mutations or imbalances of lncRNAs can lead to several diseases, including...
BACKGROUND
Long non-coding RNA (lncRNA) plays a crucial role in various biolog-ical processes, and mutations or imbalances of lncRNAs can lead to several diseases, including cancer, Prader-Willi syndrome, autism, Alzheimer's disease, cartilage-hair hypoplasia, and hear-ing loss. Understanding lncRNA-protein interactions (LPIs) is vital for elucidating basic cellular processes, human diseases, viral replication, transcription, and plant pathogen resistance. Despite the development of several LPI calculation methods, predicting LPI remains challenging, with the selection of variables and deep learning structure being the focus of LPI research.
METHODS
We propose a deep learning framework called AR-LPI, which extracts sequence and secondary structure features of proteins and lncRNAs. The framework utilizes an auto-encoder for feature extraction and employs SE-ResNet for prediction. Additionally, we apply transfer learning to the deep neural network SE-ResNet for predicting small-sample datasets.
RESULTS
Through comprehensive experimental comparison, we demonstrate that the AR-LPI ar-chitecture performs better in LPI prediction. Specifically, the accuracy of AR-LPI increases by 2.86% to 94.52%, while the F-value of AR-LPI increases by 2.71% to 94.73%.
CONCLUSION
Our experimental results show that the overall performance of AR-LPI is better than that of other LPI prediction tools.
PubMed: 38591194
DOI: 10.2174/0122115366288068240322064431 -
BioRxiv : the Preprint Server For... Mar 2024Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions,...
Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
PubMed: 38586056
DOI: 10.1101/2024.03.26.586689 -
Neuroendocrinology Apr 2024Introduction Exposure to social trauma may alter engagement with both fear-related and unrelated social stimuli long after. Intriguingly, how simultaneous discrimination...
Introduction Exposure to social trauma may alter engagement with both fear-related and unrelated social stimuli long after. Intriguingly, how simultaneous discrimination of social fear and safety is affected in neurodevelopmental conditions remains underexplored. The role of the neuropeptide oxytocin is established in social behaviors, and yet unexplored during such a challenge post-social trauma. Methods Using Magel2 knockout mice, an animal model of Prader Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SYS), we tested memory of social fear and safety after a modified social fear conditioning task. Additionally, we tracked the activity of oxytocin neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus by fibre photometry, as animals were simultaneously presented with a choice between a fear and safe social cue during recall. Results Male Magel2 KO mice trained to fear females with electrical footshocks avoided both unfamiliar females and males during recalls, lasting even a week post-conditioning. On the contrary, trained Magel2 WT avoided only females during recalls, lasting days rather than a week post-conditioning. Inability to overcome social fear and avoidance of social safety in Magel2 KO mice were associated with reduced engagement of oxytocin neurons in the SON, but not the PVN. Conclusion In a preclinical model of PWS/SYS, we demonstrated region-specific deficit in oxytocin neuron activity associated with behavioral generalization of social fear to social safety. Insights from this study add to our understanding of oxytocin action in the brain at the intersection of social trauma and PWS/SYS.
PubMed: 38574475
DOI: 10.1159/000538437 -
Molecular Psychiatry Apr 2024A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder...
Differential DNA methylation in iPSC-derived dopaminergic neurons: a step forward on the role of SNORD116 microdeletion in the pathophysiology of addictive behavior in Prader-Willi syndrome.
INTRODUCTION
A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons.
METHODS
We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT.
RESULTS
The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation.
CONCLUSION
SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.
PubMed: 38561465
DOI: 10.1038/s41380-024-02542-4 -
Global Qualitative Nursing Research 2024Mothers' experiences of caring for children with Prader-Willi Syndrome (PWS) is largely unknown. With no treatment for PWS, parents undertake (extra)ordinary care...
Mothers' experiences of caring for children with Prader-Willi Syndrome (PWS) is largely unknown. With no treatment for PWS, parents undertake (extra)ordinary care practices to keep children safe from overeating and self harm. Knowledge of these care practices could lead to effective interventions. Narrative inquiry was used to study everyday experience with Canadian mothers. Participants cared for a child 3 to 17 years old who had hyperphagia. Participants were interviewed 8 to 12 times each over the course of a year. Narrative accounts were co-composed through a collaborative process of analysis. Engaging with participants' everyday experiences amplified complex care needs for families and gaps in health and social care systems. Narrative threads focused on engaging in (extra)ordinary care practices, rigid care work to keep children healthy and safe, tension from others while enacting these care practices, and difficulty conforming to social expectations with childrearing and care work. Recommendations for practice and policy include (a) shifting from untenable care practices, (b) reconceptualizing care work, and (c) alternative care models.
PubMed: 38559700
DOI: 10.1177/23333936241242929 -
Journal of Clinical Sleep Medicine :... Apr 2024The effect of recombinant human growth hormone (rhGH) on sleep-disordered breathing (SDB) in Malaysian children with Prader-Willi syndrome (PWS) is under-investigated....
STUDY OBJECTIVES
The effect of recombinant human growth hormone (rhGH) on sleep-disordered breathing (SDB) in Malaysian children with Prader-Willi syndrome (PWS) is under-investigated. We determined (a) the short- and long-term effects of rhGH and (b) factors associated with worsening SDB, in children with PWS on rhGH.
METHODS
This retrospective study included children with PWS (with and without rhGH) who had at least one polysomnography (PSG). Outcomes measured were the presence of SDB: before and after starting rhGH and the progress of SDB with and without rhGH. Serial insulin-like growth factor-1 (IGF-1) measurements were recorded.
RESULTS
One-hundred and thirteen PSGs were analyzed. The majority (92.3%) of initial PSGs had SDB with AHI median (IQR) 5.0 (2.6,16.3) events/h. The age for receiving rhGH was median (IQR) 1.9 (0.7, 3.4) years old. A third (36.8%) had worsening SDB after initiating rhGH, which was associated with higher IGF-1 levels post-rhGH (p=0.007). After a median of 5 years of rhGH, 73.6% maintained or reduced their positive airway pressure (PAP) settings. Without rhGH, 80% had increased their PAP settings. Worsening SDB while on rhGH was associated with higher BMI, lower rhGH dose, higher IGF-1 levels and non-15q deletion.
CONCLUSIONS
Majority of Malaysian children with PWS had SDB. At initiation rhGH, one-third of patients had worsening SDB, associated with increased IGF-1 levels. Stabilization of SDB was more frequently seen in those on long-term rhGH. Worsening SDB while on rhGH was associated with a higher BMI, on a lower dose of rhGH, higher IGF-1 levels and non-15q deletion.
PubMed: 38557309
DOI: 10.5664/jcsm.11140 -
Acta Neuropathologica Mar 2024Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of...
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.
Topics: Humans; Mice; Animals; Prader-Willi Syndrome; Microglia; Carrier Proteins; Phenotype; Phagosomes; Adaptor Proteins, Signal Transducing
PubMed: 38556574
DOI: 10.1007/s00401-024-02714-0 -
Endocrinologia, Diabetes Y Nutricion Feb 2024Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity, occurring in approximately 1 in 15,000 newborns. It results from the lack of expression of genes... (Review)
Review
Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity, occurring in approximately 1 in 15,000 newborns. It results from the lack of expression of genes on the paternal allele of the chromosomal region 15q-11q13 (65-75% due to type 1 or type 2 deletion). Individuals with PWS experience associated symptoms such as hypotonia, hyperphagia, and early-onset obesity (before 5 years of age). Around 20% of adults with PWS also develop type 2 diabetes. Previous studies have shown the beneficial effects of GLP1-RA medications, such as exenatide and liraglutide, in treating type 2 diabetes in PWS. However, there is limited information available on the use of semaglutide in PWS. This study aimed to evaluate the effects of semaglutide on weight loss and glycaemic control in four patients with PWS and type 2 diabetes associated with obesity. The patients were started on weekly subcutaneous progressive doses of semaglutide.
Topics: Adult; Humans; Infant, Newborn; Prader-Willi Syndrome; Diabetes Mellitus, Type 2; Glycemic Control; Obesity; Weight Loss; Glucagon-Like Peptides
PubMed: 38553173
DOI: 10.1016/j.endien.2023.12.001 -
Journal of Personalized Medicine Mar 2024We present a series of microdeletion and microduplication syndromes (MMSs) observed in our clinical practice over a three-year period from 2020 to 2023. Microdeletion...
We present a series of microdeletion and microduplication syndromes (MMSs) observed in our clinical practice over a three-year period from 2020 to 2023. Microdeletion and microduplication syndromes, characterized by chromosomal deletions or duplications of less than five megabases, pose challenges in terms of diagnosis, especially prenatal and clinical management. Clinically, MMSs encompass a broad spectrum of manifestations, ranging from intellectual disability and developmental delays to congenital anomalies, facial dysmorphisms, and neurobehavioral abnormalities. Notable examples include well-characterized syndromes such as DiGeorge syndrome (22q11.2 deletion), Prader-Willi syndrome (15q11-q13 deletion), and Williams syndrome (7q11 deletion). Our study focuses on the genetic foundations and prenatal ultrasound findings of these syndromes, with an emphasis on cases associated with intellectual disability. Using SNP array technology, we delve into the evolving landscape of diagnostic methods, providing a nuanced understanding of copy number variations (CNVs) and their implications. Prenatal diagnosis allows for the early detection of MMSs, enabling parents and healthcare providers to make informed decisions about the pregnancy and plan for appropriate medical care and interventions. Beyond theoretical considerations, our article bridges the gap between research and practical application by offering insights derived from clinical cases. Through the presentation of specific cases, we aim to contribute valuable data to the broader discourse on MMSs, fostering knowledge exchange and enhancing the medical community's awareness of these complex genetic conditions.
PubMed: 38541032
DOI: 10.3390/jpm14030290