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ABSTRACT: Wolfram syndrome 1 (WS1) is a rare, autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, insulin-dependent diabetes mellitus, optic atrophy, and deafness resulting from loss-of-function genetic variants in the WFS1 gene. Individuals with WS1 manifest a spectrum of neuropsychiatric disorders. Here, we report a pediatric case of WS1, which stemmed from a novel biallelic WFS1 loss-of-function genetic variant. The individual initially presented with obsessive-compulsive disorder, which was successfully managed by fluvoxamine. After 2 months, the child manifested excessive daytime sleepiness. Clinical evaluation and sleep recordings revealed a diagnosis of narcolepsy type 2. Excessive daytime sleepiness was improved with methylphenidate. To the best of our knowledge, this is the first report of narcolepsy in WS1, which possibly arose during a progressive neurodegenerative process. We emphasize the need for in-depth screening for neuropsychiatric phenotypes and sleep-related disorders in WS1, for clinical management, which significantly improves the quality of life.
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Narcolepsia , Trastorno Obsesivo Compulsivo , Síndrome de Wolfram , Humanos , Femenino , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Síndrome de Wolfram/fisiopatología , Síndrome de Wolfram/complicaciones , Narcolepsia/diagnóstico , Narcolepsia/fisiopatología , Narcolepsia/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/fisiopatología , Niño , Proteínas de la Membrana/genéticaRESUMEN
Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G>A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G>C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients.
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Diagnóstico Precoz , Proteínas de la Membrana , Síndrome de Wolfram , Humanos , Síndrome de Wolfram/genética , Síndrome de Wolfram/diagnóstico , Proteínas de la Membrana/genética , Adulto , Masculino , Variación Genética , Femenino , Atrofia Óptica/genética , Atrofia Óptica/diagnósticoRESUMEN
Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.
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Calcio , Retículo Endoplásmico , Proteínas de la Membrana , Mitocondrias , Neuronas , Síndrome de Wolfram , Síndrome de Wolfram/metabolismo , Síndrome de Wolfram/genética , Calcio/metabolismo , Mitocondrias/metabolismo , Retículo Endoplásmico/metabolismo , Animales , Neuronas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Humanos , Adenosina Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Ratones Noqueados , NAD/metabolismo , Señalización del CalcioRESUMEN
Background: Wolfram syndrome (WFS) is an autosomal recessive disorder that often leads to diabetes, optic atrophy, and sensorineural hearing loss. The aim of this study was to determine the clinical characteristics and the genetic cause of the first two Moroccan families presenting with WFS. Methods: The clinical features of five members of two WFS families were evaluated. Whole-exome sequencing was conducted to explore the underlying genetic cause in the affected patients. Results: Two homozygous variants in the WFS1 gene were identified, each in one of the two families studied: a missense c.1329C>G variant (p.Ser443Arg) and a nonsense mutation c.1113G>A (p.Trp371Ter). These variants affected conserved amino acid residues, segregated well in the two families, and are absent from genetic databases and in controls of Moroccan origin. Bioinformatics analysis classified the two variants as pathogenic by in silico tools and molecular modeling. Conclusion: Our study identified for the first time two variants in Moroccan patients with WFS that extends the mutational spectrum associated with the disease.
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Proteínas de la Membrana , Mutación Missense , Linaje , Síndrome de Wolfram , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Codón sin Sentido/genética , Secuenciación del Exoma/métodos , Homocigoto , Proteínas de la Membrana/genética , Marruecos , Mutación , Mutación Missense/genética , Síndrome de Wolfram/genética , Adulto JovenRESUMEN
BACKGROUND: Wolfram-like syndrome (WFLS) is an autosomal dominant inherited disease characterized by a single heterozygous pathogenic variant in the WFS1 gene. Its clinical presentation is similar to autosomal recessive Wolfram syndrome. CASE PRESENTATION: We reported a case of a 10-year-old boy and his family members who initially experienced hearing impairment (HI), followed by optic atrophy. Genetic testing revealed the presence of a WFS1 variant (chr4-6302385 exon8 NM_006005.3: c.2590G > A, p. Glu864Lys). CONCLUSION: Wolfram-like syndrome, a rare neurodegenerative genetic disorder, manifested as deafness, optic atrophy, and diabetes mellitus. There hasn't been a definite treatment yet. Early identification of the variant in the WFS1 gene is beneficial for genetic counseling.
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Proteínas de la Membrana , Linaje , Síndrome de Wolfram , Humanos , Masculino , Proteínas de la Membrana/genética , Niño , Síndrome de Wolfram/genética , Síndrome de Wolfram/diagnóstico , Atrofia Óptica/genética , Atrofia Óptica/diagnóstico , Análisis Mutacional de ADN , MutaciónRESUMEN
OBJECTIVES: Wolfram syndrome is characterised by insulin-dependent diabetes (IDDM), diabetes insipidus (DI), optic atrophy, sensorineural deafness and neurocognitive disorders. The DIDMOAD acronym has been recently modified to DIDMOAUD suggesting the rising awareness of the prevalence of urinary tract dysfunction (UD). End stage renal disease is the commonest cause of mortality in Wolfram syndrome. We present a case series with main objective of long term follow up in four children having Wolfram syndrome with evaluation of their urodynamic profile. METHODS: A prospective follow up of four genetically proven children with Wolfram syndrome presenting to a tertiary care pediatric diabetes clinic in Pune, India was conducted. Their clinical, and urodynamic parameters were reviewed. RESULTS: IDDM, in the first decade, was the initial presentation in all the four children (three male and one female). Three children had persistent polyuria and polydipsia despite having optimum glycemic control; hence were diagnosed to have DI and treated with desmopressin. All four patients entered spontaneous puberty. All patients had homozygous mutation in WFS1 gene; three with exon 8 and one with exon 6 novel mutations. These children with symptoms of lower urinary tract malfunction were further evaluated with urodynamic studies; two of them had hypocontractile detrusor and another had sphincter-detrusor dyssynergia. Patients with hypocontractile bladder were taught clean intermittent catheterization and the use of overnight drain. CONCLUSIONS: We report a novel homozygous deletion in exon 6 of WFS-1 gene. The importance of evaluation of lower urinary tract malfunction is highlighted by our case series. The final bladder outcome in our cases was a poorly contractile bladder in three patients.
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Urodinámica , Síndrome de Wolfram , Adolescente , Niño , Femenino , Humanos , Masculino , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Estudios de Seguimiento , Proteínas de la Membrana/genética , Mutación , Pronóstico , Estudios Prospectivos , Síndrome de Wolfram/genética , Síndrome de Wolfram/complicaciones , Síndrome de Wolfram/fisiopatologíaRESUMEN
Wolfram syndrome is a rare autosomal recessive disorder affecting approximately 1 in 500,000 individuals. The disorder is most commonly caused by mutations in the WFS1 gene, which encodes an endoplasmic reticulum protein, wolframin, which is thought to protect against endoplasmic reticulum stress-related apoptosis. The major clinical findings of Wolfram syndrome are diabetes mellitus and optic atrophy, both of which usually appear before 16 years of age. Common additional findings include sensorineural hearing impairment, central diabetes insipidus, nonautoimmune hypothyroidism, delayed puberty, neurogenic bladder, cerebellar ataxia, and psychiatric disorders. Central sleep apnea is an uncommon but serious feature of Wolfram syndrome. However, the clinical details of this manifestation have not been documented. Herein, we report an adolescent with recently diagnosed Wolfram syndrome who demonstrated severe central sleep apnea on polysomnography testing. CITATION: Harris JC, Kenkare JD, Schramm CM. An adolescent with Wolfram syndrome and central sleep apnea. J Clin Sleep Med. 2024;20(7):1205-1208.
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Polisomnografía , Apnea Central del Sueño , Síndrome de Wolfram , Humanos , Síndrome de Wolfram/genética , Síndrome de Wolfram/complicaciones , Síndrome de Wolfram/fisiopatología , Síndrome de Wolfram/diagnóstico , Adolescente , Apnea Central del Sueño/genética , Apnea Central del Sueño/fisiopatología , Apnea Central del Sueño/complicaciones , MasculinoRESUMEN
Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disease with a devastating array of symptoms, including diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss, and neurological dysfunction. The discovery of the causative gene, WFS1, has propelled research on this disease. However, a comprehensive understanding of the function of WFS1 remains unknown, making the development of effective treatment a pressing challenge. To bridge these knowledge gaps, disease models for Wolfram syndrome are indispensable, and understanding the characteristics of each model is critical. This review will provide a summary of the current knowledge regarding WFS1 function and offer a comprehensive overview of established disease models for Wolfram syndrome, covering animal models such as mice, rats, flies, and zebrafish, along with induced pluripotent stem cell (iPSC)-derived human cellular models. These models replicate key aspects of Wolfram syndrome, contributing to a deeper understanding of its pathogenesis and providing a platform for discovering potential therapeutic approaches.
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Atrofia Óptica , Síndrome de Wolfram , Humanos , Ratas , Ratones , Animales , Síndrome de Wolfram/genética , Síndrome de Wolfram/terapia , Síndrome de Wolfram/diagnóstico , Pez Cebra , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Mutación , Proteínas de Unión a Calmodulina/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismoRESUMEN
Pancreatic ß-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 ß cell specific Wfs1 knockout were applied to model ß-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS ß-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted ß-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to ß-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS ß-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 ß-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with ß-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.
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Células Secretoras de Insulina , Síndrome de Wolfram , Ratones , Animales , Humanos , Síndrome de Wolfram/genética , Síndrome de Wolfram/metabolismo , Síndrome de Wolfram/patología , Células Secretoras de Insulina/metabolismo , Ratones NoqueadosRESUMEN
Different from classical autosomal recessive Wolfram syndrome, Wolfram-like syndrome is an autosomal dominant disorder caused by a heterozygous mutation in the WFS1 gene. In this case, a 7-year-old male child presented to the eye clinic due to vision loss that could not be corrected, discovered during a routine examination. The child had experienced hearing impairment since early childhood, leading to cochlear implantation. Ophthalmic examination revealed optic disc atrophy in both eyes. Optical coherence tomography imaging demonstrated a distinctive thickening of the outer plexiform layer with abnormal layering, characteristic of a single mutation in the WFS1 gene. Subsequent genetic testing identified a de novo heterozygous missense mutation c.2051C>T (p.A684V) in the WFS1 gene, which ultimately led to the diagnosis of Wolfram-like syndrome.
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Atrofia Óptica , Síndrome de Wolfram , Niño , Humanos , Masculino , Mutación , Atrofia Óptica/genética , Linaje , Tungsteno , Síndrome de Wolfram/genética , Síndrome de Wolfram/diagnósticoRESUMEN
Wolfram syndrome type 1 is a rare autosomal recessive genetic disorder which is characterized by the co-existence of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, and hence is also referred to as the acronym DIDMOAD. In this neuroimage, the typical neuroimaging features of a genetically confirmed case of Wolfram syndrome type 1 are presented. The presence of left-sided vestibulocochlear dysplasia is a novel finding in our case which has not been reported previously.
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Neuroimagen , Síndrome de Wolfram , Humanos , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Neuroimagen/métodos , Síndrome de Wolfram/diagnóstico por imagen , Síndrome de Wolfram/genética , Síndrome de Wolfram/complicacionesRESUMEN
BACKGROUND: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. METHODS: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. RESULTS: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. CONCLUSION: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM.
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Diabetes Mellitus Tipo 1 , Síndrome de Wolfram , Adolescente , Niño , Preescolar , Humanos , Lactante , Anticuerpos , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/diagnóstico , Mutación , Estudios Prospectivos , Síndrome de Wolfram/diagnósticoRESUMEN
The selection and optimization of appropriate adaptive responses depends on interoceptive and exteroceptive stimuli as well as on the animal's ability to switch from one behavioral strategy to another. Although growing evidence indicate that dopamine D2R-mediated signaling events ensure the selection of the appropriate strategy for each specific situation, the underlying neural circuits through which they mediate these effects are poorly characterized. Here, we investigated the role of D2R signaling in a mesolimbic neuronal subpopulation expressing the Wolfram syndrome 1 (Wfs1) gene. This subpopulation is located within the nucleus accumbens, the central amygdala, the bed nucleus of the stria terminalis, and the tail of the striatum, all brain regions critical for the regulation of emotions and motivated behaviors. Using a mouse model carrying a temporally controlled deletion of D2R in WFS1-neurons, we demonstrate that intact D2R signaling in this neuronal population is necessary to regulate homeostasis-dependent food-seeking behaviors in both male and female mice. In addition, we found that reduced D2R signaling in WFS1-neurons impaired active avoidance learning and innate escape responses. Collectively, these findings identify a yet undocumented role for D2R signaling in WFS1-neurons as a novel effector through which dopamine optimizes appetitive behaviors and regulates defensive behaviors.
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Dopamina , Síndrome de Wolfram , Animales , Femenino , Masculino , Reacción de Prevención , Neuronas/fisiología , Receptores de Dopamina D1 , Receptores de Dopamina D2/genéticaRESUMEN
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.
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Diabetes Mellitus Tipo 2 , Enfermedades Neurodegenerativas , Atrofia Óptica , Síndrome de Wolfram , Humanos , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Calidad de Vida , Mutación/genética , Atrofia Óptica/genéticaRESUMEN
Aim: Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, 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 Wfs1 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 ß-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.
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Células Secretoras de Insulina , Síndrome de Wolfram , Humanos , Ratas , Animales , Lactante , Incretinas/farmacología , Síndrome de Wolfram/tratamiento farmacológico , Péptido 1 Similar al Glucagón/farmacología , Polipéptido Inhibidor GástricoRESUMEN
The Wolfram syndrome 1 gene (WFS1) 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 WFS1 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on WFS1 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 WFS1, namely rs1046322, influenced the affinity of miR-668 to WFS1 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 WFS1 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 (ß=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (ß=3.163, P-value=0.0197, Pemp=0.0388) and triglyceride, TGL (ß=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/m2], 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 WFS1 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.
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Diabetes Mellitus Tipo 2 , MicroARNs , Obesidad , Síndrome de Wolfram , Niño , Humanos , Sitios de Unión/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Estudio de Asociación del Genoma Completo , MicroARNs/genética , Obesidad/epidemiología , Obesidad/genética , Pueblos del Sudeste Asiático , Síndrome de Wolfram/epidemiología , Síndrome de Wolfram/genéticaRESUMEN
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 WFS1 gene, whereas WFS2, which is more uncommon, is caused by mutations in the CISD2 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 WFS1 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 WFS1 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 WFS1 mutations, and these differences cannot be attributed solely to the positions of mutations in the WFS1 gene. The present review gives a broader overview of the results from genomic studies on the WFS1 mouse model.
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Atrofia Óptica , Síndrome de Wolfram , Animales , Ratones , Humanos , Síndrome de Wolfram/genética , Calidad de Vida , Atrofia Óptica/genética , Mutación , GenómicaRESUMEN
BACKGROUND: Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by juvenile onset diabetes, optic nerve atrophy and other systemic manifestations. Symptoms of the disease arise mostly in early childhood with a high mortality rate due to severe neurological complications. Two causative genes have been identifed in this syndrome; the classical form is caused by autosomal recessive mutations of the WFS1 gene, and a smaller portion of patients has mutations in the CIDS2 gene, which are responsible for autosomal recessive Wolfram syndrome 2. CASE PRESENTATION: We report the case of a 28-year-old Moroccan boy born from consanguineous parents referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of Wolfram syndrome was made based on insulin-dependent diabetes, optic nerve atrophy, sensorineural deafness, urological abnormalities and psychiatric illness. To establish the diagnosis at a molecular level, we performed next-generation sequencing in the index patient, which revealed compound heterozygous WFS1 mutations: c.1113G > A (p.Trp371Ter) and c.1223_1224insGGAACCACCTGGAGCCCTATGCCCATTT (p.Phe408fs). This second variant has never been described in patients with Wolfram syndrome. CONCLUSION: The identification of the genetic substrate in our patient confirmed the clinical diagnosis of Wolfram syndrome and allowed us to provide him an appropriate management and genetic counseling to his family.
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Diabetes Mellitus Tipo 1 , Atrofia Óptica , Síndrome de Wolfram , Preescolar , Masculino , Niño , Humanos , Adulto , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Mutación , AtrofiaRESUMEN
Wolfram syndrome is a monogenic disease mainly caused by mutations in the WFS1 gene. Mutations in the WFS1 gene give rise to diabetes. Here, we characterized mutant WFS1 proteins by studying the stability of full-length wild-type (WT) WFS1, a missense mutant P724L, and two C-terminally truncated mutants, W837X and Y652X. We compared their stability by overexpressing them in MIN6 and HEK293T cells. The C-terminally truncated mutants W837X and Y652X are degraded more rapidly than the missense P724L mutant or wild-type WFS1 in MIN6 cells. In contrast, Y652X is more stable than WT or other mutant WFS1 proteins in HEK293T. In conclusion, we found that C-terminally truncated WFS1 mutants are selectively degraded in a cell type-specific manner.