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BMB Reports May 2024In the context of aging, the susceptibility to infectious diseases increases, leading to heightened morbidity and mortality. This phenomenon, termed immunosenescence, is...
In the context of aging, the susceptibility to infectious diseases increases, leading to heightened morbidity and mortality. This phenomenon, termed immunosenescence, is characterized by dysregulation in the aging immune system, including abnormal alterations in lymphocyte composition, elevated basal inflammation, and the accumulation of senescent T cells. Such changes contribute to increased autoimmune diseases, enhanced infection severity, and reduced responsiveness to vaccines. Utilizing aging animal models becomes imperative for a comprehensive understanding of immunosenescence, given the complexity of aging as a physiological process in living organisms. Our investigation focuses on Cisd2, a causative gene for Wolfram syndrome, to elucidate on immunosenescence. Cisd2 knockout (KO) mice, serving as a model for premature aging, exhibit a shortened lifespan with early onset of aging-related features, such as decreased bone density, hair loss, depigmentation, and optic nerve degeneration. Intriguingly, we found that the Cisd2 KO mice present a higher number of neutrophils in the blood; however, isolated neutrophils from these mice display functional defects. Through mass spectrometry analysis, we identified an interaction between Cisd2 and Calnexin, a protein known for its role in protein quality control. Beyond this function, Calnexin also regulates calcium homeostasis through interaction with sarcoendoplasmic reticulum calcium transport ATPase (SERCA). Our study proposes that Cisd2 modulates calcium homeostasis via its interaction with Calnexin and SERCA, consequently influencing neutrophil functions. [BMB Reports 2024; 57(5): 256-261].
Topics: Animals; Neutrophils; Homeostasis; Mice, Knockout; Mice; Calcium; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Membrane Proteins
PubMed: 38627949
DOI: 10.5483/BMBRep.2024-0011 -
Frontiers in Endocrinology 2024
Topics: Child; Humans; Wolfram Syndrome; Endocrinology
PubMed: 38562411
DOI: 10.3389/fendo.2024.1384549 -
Journal of Clinical Medicine Mar 2024: Myocarditis is frequently a sporadic disease, but may also occur in the context of genetic disorders which may increase susceptibility to cardiac inflammation. Cardiac... (Review)
Review
: Myocarditis is frequently a sporadic disease, but may also occur in the context of genetic disorders which may increase susceptibility to cardiac inflammation. Cardiac involvement in Wolfram syndrome type 1 (WS1) has been scarcely characterized. To our knowledge, no cases of virus-negative myocarditis have been reported in the WS1 pediatric population. : We report the description of a pediatric case of acute myocarditis in the context of WS1, followed by a literature review of cardiovascular involvement associated with wolframin variants, and discuss potential pathophysiological mechanisms and therapeutic options. : A young patient with WS1, treated with insulin and liraglutide, was admitted for acute chest pain. Cardiac magnetic resonance and endomyocardial biopsy were performed to confirm the clinical suspicion of myocarditis. While congenital heart diseases and arrhythmias have been described previously in patients with WS1, this is the first description of virus-negative myocarditis. : Myocarditis may represent a possible manifestation of cardiovascular involvement in WS1. Cardiovascular screening may be considered in patients with WS1.
PubMed: 38542026
DOI: 10.3390/jcm13061803 -
Cell Death and Differentiation Mar 2024Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in...
Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS β-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed β-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with β-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.
Topics: Mice; Animals; Humans; Wolfram Syndrome; Insulin-Secreting Cells; Mice, Knockout
PubMed: 38321214
DOI: 10.1038/s41418-024-01258-w -
Frontiers in Genetics 2023Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2...
Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2 diabetes. Hence, genetic testing is the most appropriate tool for obtaining an accurate diagnosis. In Tunisia, few cohorts of MD have been investigated until now. The aim of this study is to search for pathogenic variants among 11 patients suspected of having MD in Tunisia using whole-exome sequencing (WES). WES was performed in 11 diabetic patients recruited from a collaborating medical center. The pathogenicity of genetic variation was assessed using combined filtering and bioinformatics prediction tools. The online ORVAL tool was used to predict the likelihood of combinations of pathogenic variations. Then, Sanger sequencing was carried out to confirm likely pathogenic predicted variants among patients and to check for familial segregation. Finally, for some variants, we performed structural modeling to study their impact on protein function. We identified novel variants related to MD in Tunisia. Pathogenic variants are located in several MODY and non-MODY genes. We highlighted the presence of syndromic forms of diabetes, including the Bardet-Biedl syndrome, Alström syndrome, and severe insulin resistance, as well as the presence of isolated diabetes with significantly reduced penetrance for Wolfram syndrome-related features. Idiopathic type 1 diabetes was also identified in one patient. In this study, we emphasized the importance of genetic screening for MD in patients with a familial history of diabetes, mainly among admixed and under-represented populations living in low- and middle-income countries. An accurate diagnosis with molecular investigation of MD may improve the therapeutic choice for better management of patients and their families. Additional research and rigorous investigations are required to better understand the physiopathological mechanisms of MD and implement efficient therapies that take into account genomic context and other related factors.
PubMed: 38162681
DOI: 10.3389/fgene.2023.1224284 -
Orphanet Journal of Rare Diseases Nov 2023Wolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic...
BACKGROUND
Wolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic atrophy, sensorineural deafness, and diabetes as the main features. Owing to clinical phenotypic heterogeneity, the misdiagnosis rate is high. However, early accurate diagnosis and comprehensive management are key to improving quality of life and prolonging life.
RESULTS
Eleven patients from seven WS pedigrees with 10 mutation sites (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, c.G2105A, and c.G1393C) in the WFS1 gene were included. We conducted further expert department analysis to clarify the diagnosis and analyze the correlation between genes and phenotypes.
CONCLUSIONS
The genotypes of these patients were closely associated with their phenotypes. The clinical data of the patients were analyzed to provide a basis for the diagnosis and clinical management of the disease.
Topics: Humans; Wolfram Syndrome; Neurodegenerative Diseases; Quality of Life; Mutation; Optic Atrophy; Diabetes Mellitus, Type 2
PubMed: 37974252
DOI: 10.1186/s13023-023-02938-5 -
Cureus Oct 2023Wolfram syndrome is a rare, multisystemic, progressive, and autosomal-recessive genetic disease, characterized by diabetes mellitus and diabetes insipidus, optic nerve...
Wolfram syndrome is a rare, multisystemic, progressive, and autosomal-recessive genetic disease, characterized by diabetes mellitus and diabetes insipidus, optic nerve atrophy, deafness, and other neurological signs. The diagnosis is usually based on history and clinical manifestations but genetic tests are necessary for confirmation. Currently, there are no treatments available to cure or delay disease progression. This report describes a case of a 23-year-old male diagnosed with Wolfram syndrome who presented to the emergency department with several episodes of loss of consciousness. This case reinforces the need for an early diagnosis of obstructive and central apneas, respiratory failure, and dysphagia, in order to prevent and treat the complications of this disease and to improve patients' quality of life.
PubMed: 37927661
DOI: 10.7759/cureus.46426 -
Frontiers in Endocrinology 2023Wolfram Syndrome (WS) is a rare condition caused by mutations in , with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1...
AIM
Wolfram Syndrome (WS) is a rare condition caused by mutations in , with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.
METHODS
Eight-month-old knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.
RESULTS
DA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.
CONCLUSION
We present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.
Topics: Humans; Rats; Animals; Infant; Incretins; Wolfram Syndrome; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide; Insulin-Secreting Cells
PubMed: 37900147
DOI: 10.3389/fendo.2023.1234925 -
Frontiers in Endocrinology 2023The Wolfram syndrome 1 gene ( is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy,...
The Wolfram syndrome 1 gene ( is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy, and deafness. Global genome-wide association studies have listed at least 19 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on play a critical role in the regulation of the wolframin protein, and loss of WFS1 function may lead to the pathogenesis of diabetes. In the Hungarian population, it was observed that a 3' UTR variant from , namely rs1046322, influenced the affinity of miR-668 to mRNA, and showed a strong association with T2D. In this study, we genotyped a large cohort of 2067 individuals of different ethnicities residing in Kuwait for the rs1046322 polymorphism. The cohort included 362 Southeast Asians (SEA), 1045 Arabs, and 660 South Asians (SA). Upon performing genetic association tests, we observed significant associations between the rs1046322 SNP and obesity traits in the SEA population, but not in the Arab or SA populations. The associated traits in SEA cohort were body mass index, BMI (β=1.562, P-value=0.0035, P), waist circumference, WC (β=3.163, P-value=0.0197, P) and triglyceride, TGL (β=0.224, P-value=0.0340). The association with BMI remained statistically significant even after multiple testing correction. Among the SEA individuals, carriers of the effect allele at the SNP had significantly higher BMI [mean of 27.63 (3.6) Kg/m], WC [mean of 89.9 (8.1) cm], and TGL levels [mean of 1.672 (0.8) mmol/l] than non-carriers of the effect allele. Our findings suggest a role for in obesity, which is a risk factor for diabetes. The study also emphasizes the significant role the ethnic background may play in determining the effect of genetic variants on susceptibility to metabolic diseases.
Topics: Child; Humans; Binding Sites; Diabetes Mellitus, Type 2; Genome-Wide Association Study; MicroRNAs; Obesity; Southeast Asian People; Wolfram Syndrome
PubMed: 37859980
DOI: 10.3389/fendo.2023.1185956 -
Biomolecules Sep 2023Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes... (Review)
Review
Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000-30,000 people are affected by WFS worldwide, and, on average, patients suffering from WFS die at 30 years of age, usually from central respiratory failure caused by massive brain atrophy. The more prevalent of the two kinds of WFS is WFS1, which is a monogenic disease and caused by the loss of the gene, whereas WFS2, which is more uncommon, is caused by mutations in the gene. Currently, there is no treatment for WFS1 to increase the life expectancy of patients, and the treatments available do not significantly improve their quality of life. Understanding the genetics and the molecular mechanisms of WFS1 is essential to finding a cure. The inability of conventional medications to treat WFS1 points to the need for innovative strategies that must address the fundamental cause: the deletion of the gene that leads to the profound ER stress and disturbances in proteostasis. An important approach here is to understand the mechanism of the cell degeneration after the deletion of the gene and to describe the differences in these mechanisms for the different tissues. The studies so far have indicated that remarkable clinical heterogeneity is caused by the variable vulnerability caused by mutations, and these differences cannot be attributed solely to the positions of mutations in the gene. The present review gives a broader overview of the results from genomic studies on the WFS1 mouse model.
Topics: Animals; Mice; Humans; Wolfram Syndrome; Quality of Life; Optic Atrophy; Mutation; Genomics
PubMed: 37759745
DOI: 10.3390/biom13091346