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Obesity Reviews : An Official Journal... May 2024The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse... (Review)
Review
Sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in panels of monogenic obesity genes from the leptin-melanocortin pathway: A systematic review.
The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse experimental designs. However, no study to date has summarized their findings. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to September 2022 to identify monogenic non-syndromic obesity gene screening studies. Of 1051 identified references, 31 were eligible after title and abstract screening and 28 after full-text reading and risk of bias and quality assessment. Most studies (82%) used NGS methods. The number of genes screened varied from 2 to 12 genes from the leptin-melanocortin pathway. While all the included studies used in silico tools to assess the functional status of mutations, only 2 performed in vitro tests. The prevalence of carriers of pathogenic/likely pathogenic monogenic mutations is 13.24% on average (heterozygous: 12.31%; homozygous/heterozygous composite: 0.93%). As no study reported the penetrance of pathogenic mutations on obesity, we estimated that homozygous carriers exhibited a complete penetrance (100%) and heterozygous carriers a variable penetrance (3-100%). The review provides an exhaustive description of sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in monogenic non-syndromic obesity genes.
PubMed: 38779716
DOI: 10.1111/obr.13754 -
Obesity Pillars Sep 2024Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality,... (Review)
Review
BACKGROUND
Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies.
METHODS
In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity.
RESULTS
Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists.
CONCLUSION
Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.
PubMed: 38766314
DOI: 10.1016/j.obpill.2024.100110 -
Psychiatry Research Jul 2024Fragile X Syndrome (FXS) results from the silencing of the FMR1 gene and is the most prevalent inherited cause of intellectual disability and the most frequent monogenic... (Review)
Review
Fragile X Syndrome (FXS) results from the silencing of the FMR1 gene and is the most prevalent inherited cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorder. It is well established that Fragile X individuals are subjected to a wide array of comorbidities, ranging from cognitive, behavioural, and medical origin. Furthermore, recent studies have also described metabolic impairments in FXS individuals. However, the molecular mechanisms linking FMRP deficiency to improper metabolism are still misunderstood. The endocannabinoidome (eCBome) is a lipid-based signalling system that regulates several functions across the body, ranging from cognition, behaviour and metabolism. Alterations in the eCBome have been described in FXS animal models and linked to neuronal hyperexcitability, a core deficit of the disease. However, the potential link between dysregulation of the eCBome and altered metabolism observed in FXS remains unexplored. As such, this review aims to overcome this issue by describing the most recent finding related to eCBome and metabolic dysfunctions in the context of FXS. A better comprehension of this association will help deepen our understanding of FXS pathophysiology and pave the way for future therapeutic interventions.
Topics: Fragile X Syndrome; Humans; Endocannabinoids; Animals; Metabolic Networks and Pathways; Fragile X Mental Retardation Protein
PubMed: 38763080
DOI: 10.1016/j.psychres.2024.115962 -
Kidney International Reports May 2024Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite... (Review)
Review
Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.
PubMed: 38707833
DOI: 10.1016/j.ekir.2024.01.053 -
Molecular Metabolism Jun 2024Metamorphosis is a transition from growth to reproduction, through which an animal adopts adult behavior and metabolism. Yet the neural mechanisms underlying the switch...
OBJECTIVE
Metamorphosis is a transition from growth to reproduction, through which an animal adopts adult behavior and metabolism. Yet the neural mechanisms underlying the switch are unclear. Here we report that neuronal E93, a transcription factor essential for metamorphosis, regulates the adult metabolism, physiology, and behavior in Drosophila melanogaster.
METHODS
To find new neuronal regulators of metabolism, we performed a targeted RNAi-based screen of 70 Drosophila orthologs of the mammalian genes enriched in ventromedial hypothalamus (VMH). Once E93 was identified from the screen, we characterized changes in physiology and behavior when neuronal expression of E93 is knocked down. To identify the neurons where E93 acts, we performed an additional screen targeting subsets of neurons or endocrine cells.
RESULTS
E93 is required to control appetite, metabolism, exercise endurance, and circadian rhythms. The diverse phenotypes caused by pan-neuronal knockdown of E93, including obesity, exercise intolerance and circadian disruption, can all be phenocopied by knockdown of E93 specifically in either GABA or MIP neurons, suggesting these neurons are key sites of E93 action. Knockdown of the Ecdysone Receptor specifically in MIP neurons partially phenocopies the MIP neuron-specific knockdown of E93, suggesting the steroid signal coordinates adult metabolism via E93 and a neuropeptidergic signal. Finally, E93 expression in GABA and MIP neurons also serves as a key switch for the adaptation to adult behavior, as animals with reduced expression of E93 in the two subsets of neurons exhibit reduced reproductive activity.
CONCLUSIONS
Our study reveals that E93 is a new monogenic factor essential for metabolic, physiological, and behavioral adaptation from larval behavior to adult behavior.
Topics: Animals; Female; Male; Adaptation, Physiological; Behavior, Animal; Circadian Rhythm; Drosophila melanogaster; Drosophila Proteins; Metamorphosis, Biological; Neurons; Transcription Factors
PubMed: 38621602
DOI: 10.1016/j.molmet.2024.101939 -
Clinical Obesity Jun 2024Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person...
Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.
Topics: Humans; Obesity; Receptor, Melanocortin, Type 4; Hyperphagia; Signal Transduction
PubMed: 38602039
DOI: 10.1111/cob.12659 -
Molecular Syndromology Mar 2024Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms...
INTRODUCTION
Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms of obesity. The " () gene encodes for a centrosomal and ciliary protein. Homozygous variants in the gene are extremely rare causes of early-onset severe monogenic obesity. Herein, we present a Turkish family with early-onset severe obesity with variable features.
METHODS
Sanger sequencing and whole-exome sequencing were performed to identify the genetic etiology in the family.
RESULTS
The index case was a 12-year-old female who presented with severe obesity (BMI of 62.7 kg/m), metabolic syndrome, and diabetic ketoacidosis. Her nonidentical twin female siblings also had early-onset severe obesity, metabolic syndrome, and diabetes. In addition, one of the affected siblings had situs inversus abdominalis, polysplenia, lumbar vertebral fusion, and abnormal lateralization. A novel homozygous nonsense (c.169C>T, p. Arg57*) pathogenic variant was detected in exon 3 of the gene in all affected members of the family. One unaffected sister and unaffected parents were heterozygous for the variant. This variant is predicted to cause a stop codon at amino acid sequence 57, leading to a truncated CEP19 protein.
DISCUSSION/CONCLUSION
Our study expands the phenotypical manifestations and variation database of variants. The findings in one of our patients reaffirm its role in the assembly and function of both motile and immotile cilia.
PubMed: 38585545
DOI: 10.1159/000535253 -
Retinal Cases & Brief Reports Apr 2024Alström Syndrome (AS) is a rare autosomal recessive monogenic ciliopathy which is caused by a mutation of the Alström syndrome 1 (ALMS1) gene. It is a multisystemic...
PURPOSE
Alström Syndrome (AS) is a rare autosomal recessive monogenic ciliopathy which is caused by a mutation of the Alström syndrome 1 (ALMS1) gene. It is a multisystemic disorder characterized by insulin resistance, childhood obesity, cardiomyopathy, progressive hepatic and renal failure, sensorineural hearing loss and retinal degeneration. Herein, we aimed to report a novel variant in ALMS1 gene causing AS in a patient presenting with visual impairment.
METHODS
Case report.
RESULTS
A 10-year-old male patient presented with photophobia and visual impairment in both eyes. Anterior and posterior segment examinations were unremarkable bilaterally. Optical coherence tomography (OCT) showed attenuated ellipsoid zone. Electroretinography revealed diminished cone and rod responses consistent with cone rod dystrophy (CRD). Genetic testing demonstrated a novel homozygous variant in ALMS1 (NM_015120.4) gene. The patient also was found to have early-stage dilated cardiomyopathy through systemic evaluation after the diagnosis of AS.
CONCLUSION
Cone-rod dystrophy in pediatric population is relatively rare condition that can be associated with syndromic ciliopathies. The authors presented a case of AS with a novel variant in ALMS1 gene based on ophthalmic findings. Ophthalmologists play an important role in the diagnosis of this syndrome and early detection of systemic manifestations.
PubMed: 38569205
DOI: 10.1097/ICB.0000000000001578 -
The Journal of Clinical Endocrinology... Apr 2024Melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity.
CONTEXT
Melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity.
OBJECTIVE
We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here, we aimed to functionally characterize these variants by analyzing four different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants.
MATERIALS AND METHODS
Cell surface expression and α-MSH- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type (WT) or variant MC4R.
RESULTS
We found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal β-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH, and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients.
DISCUSSION
We show that these obesity-associated MC4R variants affect MC4R signaling differently, yet leading to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment.
PubMed: 38567654
DOI: 10.1210/clinem/dgae210 -
Journal of Diabetes Research 2024Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop...
INTRODUCTION
Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop type 2 diabetes (T2D); however, little is known about the genetic and pathophysiological background at young age. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion. We also wanted to investigate adolescents with insulin secretion disorder more closely and analyze possible candidate genes of diabetes in a subcohort.
METHODS
We included children and adolescents with obesity who completed an oral glucose tolerance test (OGTT, glucose + insulin) in the outpatient clinic. We calculated Matsuda index, the area under the curve (AUC (Ins/Glu)), and an oral disposition index (ISSI-2) to estimate insulin resistance and beta-cell function. We identified patients with IGR and low insulin secretion (maximum insulin during OGTT < 200 mU/l) and tested a subgroup using next generation sequencing to identify possible mutations in 103 candidate genes.
RESULTS
The total group consisted of 903 children and adolescents with obesity. 4.5% showed impaired fasting glucose, 9.4% impaired glucose tolerance, and 1.2% T2D. Matsuda index and Total AUC (Ins/Glu) showed a hyperbolic relationship. Out of 39 patients with low insulin secretion, we performed genetic testing on 12 patients. We found five monogenetic defects (ABCC8 ( = 3), GCK ( = 1), and GLI2/PTF1A ( = 1)).
CONCLUSION
Using surrogate parameters of beta-cell function and insulin resistance can help identify patients with insulin secretion disorder. A prevalence of 40% mutations of known diabetes genes in the subgroup with low insulin secretion suggests that at least 1.7% of patients with adolescent obesity have monogenic diabetes. A successful molecular genetic diagnosis can help to improve individual therapy.
Topics: Humans; Child; Adolescent; Pediatric Obesity; Insulin Resistance; Diabetes Mellitus, Type 2; Insulin Secretion; Insulin; Glucose; Molecular Biology; Blood Glucose
PubMed: 38550917
DOI: 10.1155/2024/5558634