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Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural‐specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high‐fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity‐induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD‐induced obesity and associated depression. Thus, a WFS1‐ZnT3‐Zn2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression. [ABSTRACT FROM AUTHOR]

Background: Diabetes is associated with the incidence and prognosis of various malignancies, most notably endometrial cancer (EC). This study investigated the connection between diabetes and EC, with a specific focus on elucidating the biological implications of the diabetes mellitus (DM)-related gene WFS1. Methods: Using the CTD, GeneCards, and GSEA databases, we identified WFS1 as a diabetes-related gene and then conducted an extensive investigation focusing on WFS1 in the context of EC. First, we identified WFS1 as the target gene and obtained EC data from the TCGA database. Then, comprehensive analyses and verification experiments, including differential expression analysis, prognostic modeling, functional enrichment analysis, gene mutation profiling, assessment of immune cell infiltration, immunophenoscore (IPS), tumor stemness index scoring, drug sensitivity analysis, single-cell transcriptomic analysis, glycolytic pathway analysis, and clinical verification, were performed to comprehensively evaluate the clinical value of WFS1 in EC. Results: The EC group had significantly lower WFS1 expression, with an AUC of 0.857 for the ROC diagnostic curve. Overall survival analysis revealed that WFS1 was an independent risk factor for EC; low WFS1 expression was correlated with a poor prognosis. Stemness index analysis revealed that decreased WFS1 expression was associated with increased tumor grade and enhanced tumor stemness, suggesting increased malignancy of EC. In addition, WFS1 expression was correlated with tumor microenvironment features such as immune cell infiltration. WFS1 was also associated with tumor drug resistance. Conclusion: EC patients with low WFS1 expression have a worse prognosis. WFS1 can be used as diagnostic and prognostic marker for EC. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is the most common modification in eukaryotic RNAs. Growing research indicates that m6A methylation is crucial for a multitude of biological processes. However, research on the m6A modifications in the regulation of porcine muscle growth is lacking. In this study, we identified differentially expressed genes in the neonatal period of muscle development between Large White (LW) and NingXiang (NX) pigs and further reported m6A methylation patterns via MeRIP-seq. We found that m6A modification regulates muscle cell development, myofibrils, cell cycle, and phosphatase regulator activity during the neonatal phase of muscle development. Interestingly, differentially expressed genes in LW and NX pigs were mainly enriched in pathways involved in protein synthesis. Furthermore, we performed a conjoint analysis of MeRIP-seq and RNA-seq data and identified 27 differentially expressed and m6A-modified genes. Notably, a typical muscle-specific envelope transmembrane protein, WFS1, was differentially regulated by m6A modifications in LW and NX pigs. We further revealed that the m6A modification accelerated the degradation of WFS1 in a YTHDF2-dependent manner. Noteworthy, we identified a single nucleotide polymorphism (C21551T) within the last exon of WFS1 that resulted in variable m6A methylation, contributing to the differing WFS1 expression levels observed in LW and NX pigs. Our study conducted a comprehensive analysis of the m6A modification on NX and LW pigs during the neonatal period of muscle development, and elucidated the mechanism by which m6A regulates the differential expression of WFS1 in the two breeds. [ABSTRACT FROM AUTHOR]

AbstractObjectiveDesignStudy sampleResultsConclusionThis study aimed to evaluate long-term cochlear implant (CI) outcomes in individuals with mono-allelic pathogenic variants in WFS1, which is associated with both Wolfram-like syndrome and DFNA6/14/38.Retrospective case series.Seven CI recipients, ranging from eight months to 58 years of age, were included in the study, including four with Wolfram-like syndrome and three with DFNA6/14/38. A total of ten cochlear implantations were performed among these subjects.At one-year post-implantation, a mean phoneme score of 90 ± 9% at 65 dB SPL in quiet was found, which remained stable up to ten years post-implantation with a mean phoneme score of 94 ± 6%. Despite these excellent outcomes, one subject achieved no speech recognition with CI and eventually became a non-user. This individual had a prolonged absence of auditory stimulation prior to implantation and encountered multiple challenges during rehabilitation.Individuals with Wolfram-like syndrome or DFNA6/14/38 demonstrate consistently good outcomes following implantation, which remain stable over time. These findings affirm cochlear implantation as an effective rehabilitation option for these individuals. Furthermore, the stable and good CI outcomes contradict the suggested link between WFS1-associated sensorineural hearing loss and auditory neuropathy. [ABSTRACT FROM AUTHOR]

Abstract This study aims to describe the ophthalmic characteristics of autosomal dominant (AD) WFS1-associated optic atrophy (AD WFS1-OA), and to explore phenotypic differences with dominant optic atrophy (DOA) caused by mutations in the OPA1-gene. WFS1-associated diseases, or ‘wolframinopathies’, exhibit a spectrum of ocular and systemic phenotypes, of which the autosomal recessive Wolfram syndrome has been the most extensively studied. AD mutations in WFS1 also cause various phenotypical changes including OA. The most common phenotype in AD WFS1-associated disease, the combination of OA and hearing loss (HL), clinically resembles the ‘plus’ phenotype of DOA. We performed a comprehensive medical record review across tertiary referral centers in the Netherlands and Belgium resulting in 22 patients with heterozygous WFS1 variants. Eighteen (82%) had HL in addition to OA. Diabetes mellitus was found in 7 (32%). Four patients had isolated OA. One patient had an unusual phenotype with anterior chamber abnormalities and malformations of the extremities. Compared to DOA, AD WFS1-OA patients had different color vision abnormalities (red-green vs blue-yellow in DOA), abnormal OPL lamination on macular OCT (absent in DOA), more generalized thinning of the retinal nerve fiber layer, and more reduced and delayed pattern reversal visual evoked potentials.

Abstract Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural‐specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high‐fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity‐induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD‐induced obesity and associated depression. Thus, a WFS1‐ZnT3‐Zn2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression.

ABSTRACT Objective: Considering the rarity and clinical and molecular diversity of Wolfram syndrome (WS), the objective of this study was to identify patients with a clinical presentation suggestive of WS following up at a single Brazilian diabetes service and analyze their clinical and molecular characteristics. Subjects and methods: The study included all patients with a clinical presentation of WS following up between 1991 and 2022 with early-onset diabetes mellitus and other WS signs and symptoms. A retrospective analysis was conducted, including patients’ age, sex, consanguinity, age at symptom onset, diagnosis of diabetes mellitus, optic atrophy, diabetes insipidus, neurological and psychiatric disorders, hearing loss, urinary disorders, hypogonadism, and WFS1 molecular analysis. Results: Eight patients were identified, all of whom were diagnosed with diabetes mellitus at an average age of 3.7 years. Optic atrophy, diabetes insipidus, and hearing loss were common, while psychiatric and neurological alterations were observed in some cases. Genetic analysis revealed pathogenic variants in homozygosity or compound heterozygosity. The most frequent variant was p. Val412Serfs29, present in five of the seven families. Conclusions: This study represents the second-largest Brazilian sample of WS and is the first cohort from a single center in Southeast Brazil. The patients had an early, severe, and complete clinical presentation. The genetic variants identified were consistent with previous literature descriptions. The variant p. Val412Serfs29 was particularly common in this cohort, highlighting its relevance in the region.

N6-methyladenosine (m6A) is the most common modification in eukaryotic RNAs. Growing research indicates that m6A methylation is crucial for a multitude of biological processes. However, research on the m6A modifications in the regulation of porcine muscle growth is lacking. In this study, we identified differentially expressed genes in the neonatal period of muscle development between Large White (LW) and NingXiang (NX) pigs and further reported m6A methylation patterns via MeRIP-seq. We found that m6A modification regulates muscle cell development, myofibrils, cell cycle, and phosphatase regulator activity during the neonatal phase of muscle development. Interestingly, differentially expressed genes in LW and NX pigs were mainly enriched in pathways involved in protein synthesis. Furthermore, we performed a conjoint analysis of MeRIP-seq and RNA-seq data and identified 27 differentially expressed and m6A-modified genes. Notably, a typical muscle-specific envelope transmembrane protein, WFS1, was differentially regulated by m6A modifications in LW and NX pigs. We further revealed that the m6A modification accelerated the degradation of WFS1 in a YTHDF2-dependent manner. Noteworthy, we identified a single nucleotide polymorphism (C21551T) within the last exon of WFS1 that resulted in variable m6A methylation, contributing to the differing WFS1 expression levels observed in LW and NX pigs. Our study conducted a comprehensive analysis of the m6A modification on NX and LW pigs during the neonatal period of muscle development, and elucidated the mechanism by which m6A regulates the differential expression of WFS1 in the two breeds.

High-fat diet (HFD), adversely affects redox and/or endoplasmic reticulum (ER) stress status in pancreatic islets and disrupts glucose homeostasis. Additionally, maternal HFD can cause metabolic disorders in offspring at an older age. Hence, we studied the impact of HFD during pregnancy and lactation on oxidative stress and ER stress indices along with the quantity of insulin produced and released by the pancreatic islets in pubertal rat offspring. For this, pregnant rats were allocated into two groups fed either with the standard (S) or high-fat (HF) diet during pregnancy and lactation. After weaning, male pups from each group consumed standard diet until puberty. At puberty, the offspring plasma levels of glucose, insulin, leptin and corticosterone were assessed along with their ability to handle a glucose load. Finally, offspring pancreases were evaluated for oxidative and ER stress biomarkers as well as for isolated islets' glucose-induced insulin release (GIR) and content. The data obtained showed that the offspring from the HF group had elevated intra-abdominal fat mass and plasma corticosterone and leptin levels, but reduced body weight. HFD also increased pancreatic MDA level, whereas it decreased catalase activity. In the HF group, protein levels of pancreatic immunoglobulin heavy-chain binding protein (BIP), CCAAT/enhancer-binding protein homologous protein (CHOP), and wolframin ER transmembrane glycoprotein (WFS1) were increased. However, glucose tolerance and homeostatic model assessment for insulin resistance (HOMA-IR) index in the HF offspring did not change. The isolated pancreatic islets of the HF group showed disturbed glucose-induced insulin release (GIR) with unchanged insulin content. It can be concluded that maternal consumption of HFD leads to a rise in pancreatic markers of oxidative and ER stress in pubertal offspring and the increased pancreatic Wolfram syndrome 1 (WFS1) level could be a crucial factor in preserving glucose homeostasis. [ABSTRACT FROM AUTHOR]

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.

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 b-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. [ABSTRACT FROM AUTHOR]

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 (β=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (β=3.163, P-value=0.0197, Pemp=0.0388) and triglyceride, TGL (β=0.224, Pvalue= 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 noncarriers 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. [ABSTRACT FROM AUTHOR]

Background: Low-frequency non-syndromic hearing loss (LFNSHL) is a rare form of hearing loss (HL). It is defined as HL at low frequencies (≤2,000 Hz) resulting in a characteristic ascending audiogram. LFNSHL is usually diagnosed postlingually and is progressive, leading to HL affecting other frequencies as well. Sometimes it occurs with tinnitus. Around half of the diagnosed prelingual HL cases have a genetic cause and it is usually inherited in an autosomal recessive mode. Postlingual HL caused by genetic changes generally has an autosomal dominant pattern of inheritance and its incidence remains unknown. Summary: To date, only a handful of genes have been found as causing LFNSHL: well-established WFS1 and, reported in some cases, DIAPH1, MYO7A, TNC, and CCDC50 (respectively, responsible for DFNA6/14/38, DFNA1, DFNA11, DFNA56, and DFNA44). In this review, we set out audiological phenotypes, causative genetic changes, and molecular mechanisms leading to the development of LFNSHL. Key Messages: LFNSHL is most commonly caused by pathogenic variants in the WFS1 gene, but it is also important to consider changes in other HL genes, which may result in similar audiological phenotype. [ABSTRACT FROM AUTHOR]

Objective: Wolfram Syndrome (WS) is a rare autosomal recessive neurodegenerative disorder caused by mutations in WFS1 or CISD2 (WFS2). We present a rare case report of pregnancy with WFS1 spectrum disorder (WFS1-SD) in our hospital and reviewed literature to provide the management of pregnancy in these patients through multi-disciplinary cooperation. Case report: A 31-year-old (gravida 6, para 1) woman with WFS1-SD conceived naturally. During the pregnancy, she adjusted insulin intermittently to control blood glucose and monitored intraocular pressure changes under the guidance of doctors without any complications. Cesarean section was delivered at 37+4 weeks of gestation due to breech position and uterine scar and the neonatal weight was 3200 g. Apgar score 10 at 1 min, 10 at 5-min and 10 at 10 min, respectively. This rare case had a good maternal and infant outcome under multidisciplinary management. Conclusion: WS is an extremely rare disease. Limited information is available on the impact and management of WS on maternal physiologic adaptation and fetal outcome. This case provide a guide for clinicians to raise awareness of this rare disease and strengthen the management of pregnancy in these patients.

Abstract Background Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. Methods We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1–NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. Results One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7–9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. Conclusions We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

AimWolfram 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.MethodsEight-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.ResultsDA-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.ConclusionWe 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.

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 (β=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (β=3.163, P-value=0.0197, Pemp=0.0388) 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/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.

The placental tissue stress of intrahepatic cholestasis of pregnancy (ICP) is activated by ERS under hypoxia condition. PERK signaling pathway is the key pathway for UPR regulation, and is first to activated during ERS. WFS1, as an important regulatory gene of UPR pathway, participates in ERS regulation. The purpose of our study is to explore the expression level and mutual regulation mechanisms of WFS1 and PERK-mediated UPR pathway in ICP placental tissue cell under stress. Blood and placenta samples were obtained from the ICP patients and ethinylestradiol (EE)-induced intrahepatic cholestasis pregnant rats. IHC and WB were used to detect the expression of WFS1, key factors of PERK pathway (GRP78, PERK, eIF2a, P-eIF2α, ATF4) and placental stress peptides (CRH, UCN). Furthermore, qPCR was carried out to detect mRNA expression of above indicators. The expression levels of WFS1 and key factors of PERK pathway were significantly increased in severe ICP placental tissues. Moreover, qPCR and WB showed that relative mRNA and protein expression levels of WFS1 and key factors of PERK pathways in placenta tissues of severe ICP and EE-induced intrahepatic cholestasis pregnant rats were higher than those in control group to varying degrees, while CRH and UCN were descended. Meanwhile, after WFS1-siRNA targeted silencing of the WFS1 gene, the protein expression levels of PERK, P-eIF2α, ATF4 were significantly increased, while CRH and UCN protein were significantly decreased. Our study revealed that the activation of WFS1 and PERK-p-eIF2α-ATF4 signaling pathway may contribute to stress regulation in placental tissue cells of intrahepatic cholestasis of pregnancy, thereby avoiding adverse pregnancy outcomes. • Firstly reported the expression of PERK-eIF2a-ATF4 pathway in ICP placental cells. • PERK-eIF2a-ATF4 pathway contributed to stress regulation in ICP placental cells. • WFS1 ensures that ER plays a normal stress function protein synthesis in ICP. • WFS1 and PERK-eIF2a-ATF4 pathway has a mutual regulation mechanism in ICP. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Wolfram-like syndrome (WFLS) is a recently described autosomal dominant disorder with phenotypic similarities to autosomal recessive Wolfram syndrome (WS), including optic atrophy, hearing impairment, and diabetes mellitus. We summarize current literature, define the clinical characteristics, and investigate potential genotype phenotype correlations. A systematic literature search was conducted in electronic databases Pubmed/MEDLINE, EMBACE, and Cochrane Library. We included studies reporting patients with a clinical picture consisting at least 2 typical clinical manifestations of WSF1 disorders and heterozygous mutations in WFS1. In total, 86 patients from 35 studies were included. The most common phenotype consisted of the combination of optic atrophy (87%) and hearing impairment (94%). Diabetes mellitus was seen in 44% of the patients. Nineteen percent developed cataract. Patients with missense mutations in WFS1 had a lower number of clinical manifestations, less chance of developing diabetes insipidus, but a younger age at onset of hearing impairment compared to patients with nonsense mutations or deletions causing frameshift. There were no studies reporting decreased life expectancy. This review shows that, within the spectrum of WFS1 -associated disorders or "wolframinopathies," autosomal dominantly inherited WFLS has a relatively mild phenotype compared to autosomal recessive WS. The clinical manifestations and their age at onset are associated with the specific underlying mutations in the WFS1 gene. [ABSTRACT FROM AUTHOR]

Wfs1 is an endoplasmic reticulum (ER) membrane located protein highly expressed in pancreatic β cells and brain. Wfs1 deficiency causes adult pancreatic β cells dysfunction following β cells apoptosis. Previous studies mainly focus on the Wfs1 function in adult mouse pancreatic β cells. However, whether Wfs1 loss-of-function impairs mouse pancreatic β cell from its early development is unknown. In our study, Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from early postnatal day 0 (P0) to 8 weeks old, with decreased percentage of β cells and increased percentage of α and δ cells. Meanwhile, Wfs1 loss-of-function leads to reduced intracellular insulin content. Notably, Wfs1 deficiency impairs Glut2 localization and causes the accumulation of Glut2 in mouse pancreatic β cell cytoplasm. In Wfs1 -deficient mice, glucose homeostasis is disturbed from early 3 weeks old to 8 weeks old. This work reveals that Wfs1 is significantly required for the composition of pancreatic endocrine cells and is essential for Glut2 localization in mouse pancreatic β cells. • Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from P0 to 8 weeks old. • Wfs1 deficiency causes the reduction of intracellular insulin content. • Wfs1 loss-of-function impairs Glut2 localization to cytomembrane. • Wfs1 -deficient mice show disturbances in glucose tolerance from 3 weeks old. [ABSTRACT FROM AUTHOR]

Background: Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. Methods: We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1–NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. Results: One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7–9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. Conclusions: We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates. [ABSTRACT FROM AUTHOR]

Abstract Background TCF7L2 rs7903146 and PNPLA3 rs738409 gene variants confer the strongest risk for type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), respectively. Pancreatic triacylglycerol content (PTGC) was reported to have a role in T2DM development. We aimed to assess the correlation between PTGC and hepatic triacylglycerol content (HTGC) stratified by PNPLA3 rs738409 genotype and subsequently interactions between PTGC and gene variants associated with β-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11ΒHSD1) on β-cell function were also tested. Methods PTGC and HTGC were assessed using MR in a post-hoc analysis of a genotype-based (PNPLA3 rs738409) recall study of 39 (lipid- and glucose lowering) drug-naïve women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11ΒHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of β-cell function. We used Spearman’s rank-order, Mann-Whitney-U tests, and linear regression models. Results PTGC and HTGC values were correlated after stratification by the rs738409 variant (only in CC genotype group R = 0.67, p = 10− 4). PTGC and HbA1c values correlated in the entire study population (R = 0.58, p = 10− 4). Insulin resistance, sensitivity and disposition indices were correlated with PTGC (HOMA2-IR: R = 0.42, p = 0.008; TyG: R = 0.38, p = 0.018; Matsuda: R= − 0.48, p = 0.002; DIbasal: R=−0.33, p = 0.039; ISSI-2: R=−0.35, p = 0.028). Surrogate markers of β-cell function (HOMA2-B, AUCinsulin/AUCglucose) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R = 0.51, p = 0.022; rs18001214: CT + CC R = 0.55, p = 0.013; rs4844880: TA + AA R = 0.56, p = 0.016. The strongest interactions were found between PTGC and TCF7L2 rs7903146 effect on HOMA2-B (p = 0.001) and AUCinsulin/AUCglucose (p = 0.013). Conclusions The PNPLA3 rs738409 genotype has a major effect on the correlation between PTGC and HTGC. Furthermore we first report the combined effect of PTGC and individual risk gene variants of TCF7L2, WFS1 and 11ΒHSD1 on β-cell dysfunction. The correlation between pancreatic lipid accumulation and HbA1c also indicates an important role for the latter pathology.

The aim of this study is to contribute to a better description of the genotypic and phenotypic spectrum of DFNA6/14/38 and aid in counseling future patients identified with this variant. Therefore, we describe the genotype and phenotype in a large Dutch–German family (W21-1472) with autosomal dominant non-syndromic, low-frequency sensorineural hearing loss (LFSNHL). Exome sequencing and targeted analysis of a hearing impairment gene panel were used to genetically screen the proband. Co-segregation of the identified variant with hearing loss was assessed by Sanger sequencing. The phenotypic evaluation consisted of anamnesis, clinical questionnaires, physical examination and examination of audiovestibular function. A novel likely pathogenic WFS1 variant (NM_006005.3:c.2512C>T p.(Pro838Ser)) was identified in the proband and found to co-segregate with LFSNHL, characteristic of DFNA6/14/38, in this family. The self-reported age of onset of hearing loss (HL) ranged from congenital to 50 years of age. In the young subjects, HL was demonstrated in early childhood. At all ages, an LFSNHL (0.25–2 kHz) of about 50–60 decibel hearing level (dB HL) was observed. HL in the higher frequencies showed inter-individual variability. The dizziness handicap inventory (DHI) was completed by eight affected subjects and indicated a moderate handicap in two of them (aged 77 and 70). Vestibular examinations (n = 4) showed abnormalities, particularly in otolith function. In conclusion, we identified a novel WFS1 variant that co-segregates with DFNA6/14/38 in this family. We found indications of mild vestibular dysfunction, although it is uncertain whether this is related to the identified WFS1 variant or is an incidental finding. We would like to emphasize that conventional neonatal hearing screening programs are not sensitive to HL in DFNA6/14/38 patients, because high-frequency hearing thresholds are initially preserved. Therefore, we suggest screening newborns in DFNA6/14/38 families with more frequency-specific methods. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of "poorly folded proteins", namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction. [ABSTRACT FROM AUTHOR]

Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural-specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high-fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn 2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity-induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD-induced obesity and associated depression. Thus, a WFS1-ZnT3-Zn 2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Diabetes is associated with the incidence and prognosis of various malignancies, most notably endometrial cancer (EC). This study investigated the connection between diabetes and EC, with a specific focus on elucidating the biological implications of the diabetes mellitus (DM)-related gene WFS1., Methods: Using the CTD, GeneCards, and GSEA databases, we identified WFS1 as a diabetes-related gene and then conducted an extensive investigation focusing on WFS1 in the context of EC. First, we identified WFS1 as the target gene and obtained EC data from the TCGA database. Then, comprehensive analyses and verification experiments, including differential expression analysis, prognostic modeling, functional enrichment analysis, gene mutation profiling, assessment of immune cell infiltration, immunophenoscore (IPS), tumor stemness index scoring, drug sensitivity analysis, single-cell transcriptomic analysis, glycolytic pathway analysis, and clinical verification, were performed to comprehensively evaluate the clinical value of WFS1 in EC., Results: The EC group had significantly lower WFS1 expression, with an AUC of 0.857 for the ROC diagnostic curve. Overall survival analysis revealed that WFS1 was an independent risk factor for EC; low WFS1 expression was correlated with a poor prognosis. Stemness index analysis revealed that decreased WFS1 expression was associated with increased tumor grade and enhanced tumor stemness, suggesting increased malignancy of EC. In addition, WFS1 expression was correlated with tumor microenvironment features such as immune cell infiltration. WFS1 was also associated with tumor drug resistance., Conclusion: EC patients with low WFS1 expression have a worse prognosis. WFS1 can be used as diagnostic and prognostic marker for EC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Ke, Xu, Wang, Wang, Tan, Wu and Cheng.)

Objective: Considering the rarity and clinical and molecular diversity of Wolfram syndrome (WS), the objective of this study was to identify patients with a clinical presentation suggestive of WS following up at a single Brazilian diabetes service and analyze their clinical and molecular characteristics., Subjects and Methods: The study included all patients with a clinical presentation of WS following up between 1991 and 2022 with early-onset diabetes mellitus and other WS signs and symptoms. A retrospective analysis was conducted, including patients' age, sex, consanguinity, age at symptom onset, diagnosis of diabetes mellitus, optic atrophy, diabetes insipidus, neurological and psychiatric disorders, hearing loss, urinary disorders, hypogonadism, and WFS1 molecular analysis., Results: Eight patients were identified, all of whom were diagnosed with diabetes mellitus at an average age of 3.7 years. Optic atrophy, diabetes insipidus, and hearing loss were common, while psychiatric and neurological alterations were observed in some cases. Genetic analysis revealed pathogenic variants in homozygosity or compound heterozygosity. The most frequent variant was p. Val412Serfs29, present in five of the seven families., Conclusions: This study represents the second-largest Brazilian sample of WS and is the first cohort from a single center in Southeast Brazil. The patients had an early, severe, and complete clinical presentation. The genetic variants identified were consistent with previous literature descriptions. The variant p. Val412Serfs29 was particularly common in this cohort, highlighting its relevance in the region., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.

Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo , WFS1 loss results in reduced ER to mitochondria calcium (Ca 2+ ) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1 E864K leads to decreases in mitochondria bioenergetics and Ca 2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1 mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS. E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS. Abbreviations: BafA1: bafilomycin A 1 ; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP 3 R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.

Background: TCF7L2 rs7903146 and PNPLA3 rs738409 gene variants confer the strongest risk for type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), respectively. Pancreatic triacylglycerol content (PTGC) was reported to have a role in T2DM development. We aimed to assess the correlation between PTGC and hepatic triacylglycerol content (HTGC) stratified by PNPLA3 rs738409 genotype and subsequently interactions between PTGC and gene variants associated with β-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11ΒHSD1) on β-cell function were also tested. Methods: PTGC and HTGC were assessed using MR in a post-hoc analysis of a genotype-based (PNPLA3 rs738409) recall study of 39 (lipid- and glucose lowering) drug-naïve women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11ΒHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of β-cell function. We used Spearman's rank-order, Mann-Whitney-U tests, and linear regression models. Results: PTGC and HTGC values were correlated after stratification by the rs738409 variant (only in CC genotype group R = 0.67, p = 10− 4). PTGC and HbA1c values correlated in the entire study population (R = 0.58, p = 10− 4). Insulin resistance, sensitivity and disposition indices were correlated with PTGC (HOMA2-IR: R = 0.42, p = 0.008; TyG: R = 0.38, p = 0.018; Matsuda: R= − 0.48, p = 0.002; DIbasal: R=−0.33, p = 0.039; ISSI-2: R=−0.35, p = 0.028). Surrogate markers of β-cell function (HOMA2-B, AUCinsulin/AUCglucose) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R = 0.51, p = 0.022; rs18001214: CT + CC R = 0.55, p = 0.013; rs4844880: TA + AA R = 0.56, p = 0.016. The strongest interactions were found between PTGC and TCF7L2 rs7903146 effect on HOMA2-B (p = 0.001) and AUCinsulin/AUCglucose (p = 0.013). Conclusions: The PNPLA3 rs738409 genotype has a major effect on the correlation between PTGC and HTGC. Furthermore we first report the combined effect of PTGC and individual risk gene variants of TCF7L2, WFS1 and 11ΒHSD1 on β-cell dysfunction. The correlation between pancreatic lipid accumulation and HbA1c also indicates an important role for the latter pathology. [ABSTRACT FROM AUTHOR]

With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six children with ANSD who underwent cochlear implantation between 2001 and 2021 were included. Comprehensive etiological analyses were conducted, including a history review, next-generation sequencing-based genetic examinations, and imaging studies using high-resolution computed tomography and magnetic resonance imaging. Serial behavioral and speech audiometry were performed before and after surgery, and the outcomes with CI were evaluated using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. By etiology, 18, 1, 1, and 10 patients had OTOF-related, WFS1-related, OPA1-related, and cochlear nerve deficiency (CND)-related ANSD, respectively. Six patients had no definite etiology. The average CI-aided behavioral threshold was 28.3 ± 7.8 dBHL, and those with CND-related ANSD were significantly worse than OTOF-related ANSD. The patients' median CAP and SIR scores were 6 and 4, respectively. Favorable CI outcomes were observed in patients with certain etiologies of ANSD, particularly those with OTOF (CAP/SIR scores 5–7/2–5), WFS1 (CAP/SIR score 6/5), and OPA1 variants (CAP/SIR score 7/5). Patients with CND had suboptimal CI outcomes (CAP/SIR scores 2–6/1–3). Identifying the etiologies in ANSD patients is crucial before surgery and can aid in predicting prognoses. [ABSTRACT FROM AUTHOR]

Abstract Background Wolfram syndrome (WFS) is a rare autosomal recessive genetic disease whose main cause is mutations in the WFS1 and CISD2 genes. Its characteristic clinical manifestations are diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Methods In this study, two patients from this particular family underwent complete routine biochemical and ophthalmic tests. Blood, urine, routine stool test, visual acuity (VA) examination, visual field assessment, funduscope, optical coherence tomography and periorbital magnetic resonance imaging (MRI) scans were performed for each patient to evaluate whether the nerve fiber layer around the optic nerve head was atrophied and next-generation sequencing of target genes was performed in two patients. Results When the patients were diagnosed with Wolfram syndrome, their genetic analyses suggested unique three-site compound heterozygous mutations (c.2314C > T + c.2194C > T + c.2171C > T) in exon 8 of both patients’ chromosome 4. One mutation (c.2314C > T) was a novel mutation in the known reports of Wolfram syndrome. As a degenerative genetic disease, the types of gene mutations in the Chinese population are generally homozygous mutations at the unit point or compound heterozygous mutations at two nucleotide change sites. However, the two patients reported in this study are the first known cases of compound heterozygous mutations with three mutation sites coexisting on the WFS1 gene in China or even globally. Conclusions This study expands the phenotypic spectrum of Wolfram syndrome and may reveal a novel mutation pattern of pathogenesis of Wolfram syndrome. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with WFS1.

Introduction: Sensorineural hearing loss is the most frequent type of hearing impairment in the human population. Genetic factors account for over 60% of hearing loss in patients. This is a genetically heterogeneous sensorineural disorder. Case Report: We carried out whole exome sequencing (WES) to screen hearing loss candidate genes in a member of an Iranian family with hearing loss. The Sanger process was used to sequencing the variant in the family members. A novel mutation (c. 559C > T) was found in the WFS1 gene (in exon 5) in the patient leading to a heterozygous missense mutation (p.L187F). Furthermore, it co-segregated with HL in the family. All affected individuals in the family had severe-to-profound HL. Conclusion: This survey is the first to describe WFS1 related HL in the Iranian population. Our data propose that the WFS1-p.L187F mutation is the pathogenic variant for autosomal dominant nonsyndromic hearing loss. Our results extend the range of the WFS1 gene mutations.

Objective:Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by non-autoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing.Methods:Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of “in silico” analyses, protein prediction, and functional consequences.Results:Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers.Conclusion:Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLAWFS1 neurons' NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders. [Display omitted] • DISC1-N mutation impacts risk assessment • BLAWFS1 neuron-astrocyte dysfunction in DISC1-N mice • Stimulating astrocytes revives BLAWFS1 neuron fire in DISC1-N • Astrocytes activation restores risk response via D-serine at NMDA receptors Zhou et al. discover that DISC1-N mice display impaired risk assessment. A specific group of glutamatergic neurons in the BLA exhibit diminished firing ability and impaired communication with astrocytes. Activation of these astrocytes reinstates neuronal excitability via these neurons' NMDA receptors, leading to improved risk-assessment behavior in these mice. [ABSTRACT FROM AUTHOR]

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD. [ABSTRACT FROM AUTHOR]

Context: Wolfram syndrome (WFS) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes, diabetes insipidus, optic atrophy, deafness, and progressive neurodegeneration. However, due to the progressive nature of the disease and a lack of complete clinical manifestations, a confirmed diagnosis of WFS at the time of onset of diabetes is a challenge. Objective: With WFS1 rare heterozygous variants reported in diabetes, there is a need for comprehensive genetic screening strategies for the early diagnosis of WFS and delineating the phenotypic spectrum associated with the WFS1 gene variants in young-onset diabetes. Methods: This case series of 11 patients who were positive for WFS1 variants were identified with next-generation sequencing (NGS)–based screening of 17 genemonogenic diabetes panel. These results were further confirmed with Sanger sequencing. Results: 9 out of 11 patients were homozygous for pathogenic/likely pathogenic variants in the WFS1 gene. Interestingly, 3 of these probands were positive for the novel WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370Serfs*173) variant, and haplotype analysis suggested a founder effect in 3 families from Southern India. Additionally, we identified 2 patients with young-onset diabetes who were heterozygous for a likely pathogenic variant or a variant of uncertain significance in the WFS1 gene. Conclusion: These results project the need for NGS-based parallel multigene testing as a tool for early diagnosis of WFS and identify heterozygous WFS1 variants implicated in young-onset diabetes. [ABSTRACT FROM AUTHOR]

Abstract Background Although the molecular function of wolframin remains unclear, the lack of this protein is known to cause stress in the endoplasmic reticulum. Some variants in the Wolfram Syndrome 1 gene (WFS1) were associated with various neuropsychiatric disorders in humans, such as aggressiveness, impulsivity and anxiety. Results Here we present an in silico study predicting a single nucleotide polymorphism (rs852850348) in the canine WFS1 gene which was verified by direct sequencing and was genotyped by a PCR-based technique. We found that the rs852850348 polymorphism is located in a putative microRNA (cfa-miR-8834a and cfa-miR-1838) binding site. Therefore, the molecular effect of allelic variants was studied in a luciferase reporter system that allowed assessing gene expression. We demonstrated that the variant reduced the activity of the reporter protein expression in an allele-specific manner. Additionally, we performed a behavioral experiment and investigated the association with this locus to different performance in this test. Association was found between food possessivity and the studied WFS1 gene polymorphism in the Border collie breed. Conclusions Based on our findings, the rs852850348 locus might contribute to the genetic risk of possessivity behavior of dogs in at least one breed and might influence the regulation of wolframin expression.

Abstract Background Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM. Case presentation In this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene. Conclusions The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition characterized by high blood glucose levels. Mutations in the WFS1 gene cause β-cell death, leading to Wolfram syndrome and diabetes. There have been few studies that have been linked to T2DM and the rs6446282 polymorphism in the WFS1 gene, and there are no studies from Saudi Arabia. As a result, the purpose of this study was to investigate the association between the rs6446482 polymorphism in the WFS1 gene and T2DM in the Saudi population. Methods: One hundred T2DM patients and 100 healthy controls were recruited based on inclusion and exclusion criteria. Genomic DNA was obtained from collected blood, and using oligonucleotides, PCR was performed followed by RFLP analysis. Statistical analysis was performed with SPSS software to compare the numerical and categorical data. Results: This case-control study compared T2DM patients to healthy controls. Age, weight, BMI, FBG, HDL-c, TC, TGs, and family history (p

The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of “poorly folded proteins”, namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction.

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.

Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in the wolframin ER transmembrane glycoprotein (WFS1) gene and characterized by diabetes mellitus, diabetes insipidus, optic atrophy and deafness. In experimental models the homozygous Wfs1 mutant mice have a full penetrance and clearly expressed phenotype, whereas heterozygous mutants have a less-pronounced phenotype between the wild-type and homozygous mutant mice. Heterozygous WFS1 mutations have been shown to be significant risk factors for diabetes and metabolic disorders in humans. In the present study we analyzed the response of heterozygous Wfs1 mice to high fat diet (HFD) by exploring potential outcomes and molecular changes induced by this challenge. The HFD treatment increased the body weight (BW) similarly both in Wfs1 wild-type (WT) and heterozygous (HZ) mice, and therefore HFD also prevented the impaired BW gain found in Wfs1 mutant mice. In Wfs1HZ mutant mice, HFD impaired the normalized insulin secretion and the expression of ER stress genes in isolated pancreatic islets. These results suggest that Wfs1HZ mice have a decreased insulin response and pronounced cellular stress response due to a higher sensitivity to HFD as hypothesized. In Wfs1HZ mice, HFD increased the expression of Ire1α and Chop in pancreas and decreased that of Ire1α and Atf4 in liver. The present study shows that HFD can disturb insulin function with an increased ER stress in Wfs1HZ mice and only one functional Wfs1 gene copy is not sufficient to compensate this challenge. In conclusion, our study indicates that quantitative Wfs1 gene deficiency is sufficient to predispose the carriers of single functional Wfs1 copy to diabetes and metabolic syndrome and makes them susceptible to the environmental challenges such as HFD. [ABSTRACT FROM AUTHOR]

Glucokinase-Maturity-Onset Diabetes of the Young (GCK -MODY) is characterized by asymptomatic, non-progressive and fasting hyperglycemia, albeit not without phenotypic variability. We used next generation sequencing (NGS) to screen for 34 MODY genes in a non-obese person with familial young-onset diabetes followed by screening in 24 family members within three generations with varying presentations of young-onset diabetes and sensorineural hearing loss. The index patient was found to carry a paternally-inherited heterozygous missense variant (c.716 A>G) of GCK in exon 7 with amino acid change (Q239R). This variant was associated with phenotypic heterogeneity ranging from normal glucose tolerance to diabetes with complications amongst the siblings which might be modified by obesity and chronic hepatitis B infection. Two paternally-inherited variants of SLC29A3 encoding a nucleoside transporter protein and Apo-A1 genes also co-segregated with glucose and lipid traits. Co-occurrence of diabetes and deafness in maternal aunts led to discovery of WFS1 (Wolfram syndrome type 1) as a cause of non-syndromic deafness in multiple members of the maternal pedigree. Our findings highlight the complex causes of familial young-onset diabetes and the need of a multidisciplinary approach to interpret the clinical relevance of discoveries made by NGS in this era of genomic medicine. [ABSTRACT FROM AUTHOR]

Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY) is characterized by asymptomatic, non-progressive and fasting hyperglycemia, albeit not without phenotypic variability. We used next generation sequencing (NGS) to screen for 34 MODY genes in a non-obese person with familial young-onset diabetes followed by screening in 24 family members within three generations with varying presentations of young-onset diabetes and sensorineural hearing loss. The index patient was found to carry a paternally-inherited heterozygous missense variant (c.716 A>G) of GCK in exon 7 with amino acid change (Q239R). This variant was associated with phenotypic heterogeneity ranging from normal glucose tolerance to diabetes with complications amongst the siblings which might be modified by obesity and chronic hepatitis B infection. Two paternally-inherited variants of SLC29A3 encoding a nucleoside transporter protein and Apo-A1 genes also co-segregated with glucose and lipid traits. Co-occurrence of diabetes and deafness in maternal aunts led to discovery of WFS1 (Wolfram syndrome type 1) as a cause of non-syndromic deafness in multiple members of the maternal pedigree. Our findings highlight the complex causes of familial young-onset diabetes and the need of a multidisciplinary approach to interpret the clinical relevance of discoveries made by NGS in this era of genomic medicine.

Background: Wolfram syndrome (WFS) is a rare autosomal recessive genetic disease whose main cause is mutations in the WFS1 and CISD2 genes. Its characteristic clinical manifestations are diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Methods: In this study, two patients from this particular family underwent complete routine biochemical and ophthalmic tests. Blood, urine, routine stool test, visual acuity (VA) examination, visual field assessment, funduscope, optical coherence tomography and periorbital magnetic resonance imaging (MRI) scans were performed for each patient to evaluate whether the nerve fiber layer around the optic nerve head was atrophied and next-generation sequencing of target genes was performed in two patients. Results: When the patients were diagnosed with Wolfram syndrome, their genetic analyses suggested unique three-site compound heterozygous mutations (c.2314C > T + c.2194C > T + c.2171C > T) in exon 8 of both patients' chromosome 4. One mutation (c.2314C > T) was a novel mutation in the known reports of Wolfram syndrome. As a degenerative genetic disease, the types of gene mutations in the Chinese population are generally homozygous mutations at the unit point or compound heterozygous mutations at two nucleotide change sites. However, the two patients reported in this study are the first known cases of compound heterozygous mutations with three mutation sites coexisting on the WFS1 gene in China or even globally. Conclusions: This study expands the phenotypic spectrum of Wolfram syndrome and may reveal a novel mutation pattern of pathogenesis of Wolfram syndrome. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with WFS1. [ABSTRACT FROM AUTHOR]

Hypothesis: About 1% of patients clinically diagnosed as type 1 diabetes have non-autoimmune monogenic diabetes. The distinction has important therapeutic implications but, given the low prevalence and high cost of testing, selecting patients to test is important. We tested the hypothesis that low genetic risk for type 1 diabetes can substantially contribute to this selection.Methods: As proof of principle, we examined by exome sequencing families with 2 or more children, recruited by the Type 1 Diabetes Genetics Consortium (T1DGC) and selected for negativity for 2 autoantibodies and absence of risk human leukocyte antigen haplotypes.Results: We examined 46 families that met the criteria. Of the 17 with an affected parent, 7 (41.2%) had actionable monogenic variants. Of 29 families with no affected parent, 14 (48.3%) had such variants, including 5 with recessive pathogenic variants of WFS1 but no report of other features of Wolfram syndrome. Our approach diagnosed 55.8% of the estimated number of monogenic families in the entire T1DGC cohort, by sequencing only 11.1% of the autoantibody-negative ones.Conclusions: Our findings justify proceeding to large-scale prospective screening studies using markers of autoimmunity, even in the absence of an affected parent. We also confirm that nonsyndromic WFS1 variants are common among cases of monogenic diabetes misdiagnosed as type 1 diabetes. [ABSTRACT FROM AUTHOR]

Abstract Background Wolfram Syndrome (WFS) is a rare autosomal recessive neurodegenerative disease which has a wide spectrum of manifestations including diabetes insipidus, diabetes mellitus, optic atrophy and deafness. WFS1 and CISD2 are two main causing genes of WFS. The aim of this study was to illustrate the ophthalmologic manifestations and determine the genotype of Chinese WFS patients. Results Completed ophthalmic examinations and family investigations were performed on 4 clinically diagnosed WFS patients from 4 unrelated families. Genetic testing was done by the next generation sequencing of candidate genes. One patient carried a homozygous mutation (c.272_273del) in CISD2, two patients carried compound heterozygous mutations (c.1618 T > G + c.2020G > A and c.1048 T > A + c.2020G > A) in WFS1, and one patient carried a heterozygous mutation (c.937C > T) in WFS1. Three of them were novel mutations. Conclusions Our study indicated WFS in Chinese is a neurodegenerative disease with both wide spectrum of clinical features and genetic heterogeneity. We found three novel mutations in WFS patients, and to our best knowledge, this is the first report of Chinese WFS patient with mutation in CISD2.