WFS1 Gene Research Articles

Assessment The effect of WFS1 gene rs734312 G/A variant with type 2 diabetes in Iraqi Arab patients

Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition characterized by high blood glucose levels. Mutations in the WFS1 gene cause b-cell death, leading to Wolfram syndrome and diabetes. Diabetes has achieved epidemic levels in Iraq over the last decade, mirroring global increases in the incidence of diabetes mellitus. The aim of this study was to investigate association of WFS1 genes polymorphism (rs734312 G/A) with T2D in Iraqi Arab patients and to improve if obese patients effect more than other patients. Methods: 100 T2D (obese – non obese) and 100 controls (obese – non obese). The RT- PCR assay Technique was used to genotype WFS1 rs734312 G/A, making use of newly-designed primers. Results: parameter's that study show significant between group. The study concluded that the WFS1 rs734312 G/A shows no significant difference in genotypes Codominant, Dominant, recessive and Additive genotype between group. The comparison between the control non obese and T2DM non obese groups (GA vs GG) significant variation was observed in codominant (0.0001). LDL showed significant between GG vs AA and LDL showed at border of significally for (GG & GA+ AA). Negative correlation between (F. G and LDL VLDL) and between (LDL, HDL and TG), between (insulin and HOMA-IR with LDL, HDL).In conclusion Through the results obtained, it was found that rs734312 G/A Although it has a considerable impact on the development of type 2 diabetes (GA vs GG), the effect has not been demonstrated in all cases. When obese diabetic patients are compared, it has no significant influence on raising the likelihood of developing type 2 diabetes.

ODP254 WFS1 Loss of Function Causes ER Stress-Mediated Inflammation in Pancreatic β-Cells

Abstract Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in the activation of apoptotic cascades. Although the terminal UPR is well known to yield an inflammatory response called "sterilized inflammation" that accelerates β-cell dysfunction and death in diabetes, the contribution of β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1-deficiency enhances the gene expression of pro-inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. Under thechronic[BL1] high-glucose condition, CRISPR/Cas9-mediated Wfs1-knockout (KO) INS-1 832/13 cells, the pancreatic β-cell model of Wolfram syndrome, showed enhanced gene expression levels of ER stress markers (Chop, sXbp1, Bip, and Txnip). Moreover, the gene expression levels of pro-inflammatory cytokines (Il-1β, Il-6), chemokine (Ccl2), and vascular endothelial growth factor A (VegfA) were higher in Wfs1- KO INS-1 832/13 cells when compared to Wfs1-wild type INS-1 832/13 cells. [BL2] The high glucose-induced pro-inflammatory cytokine genes in Wfs1-KO INS-1 832/13 cells were mediated by the PKR-like ER-resident kinase (PERK) and inositol-requiring enzyme 1α (IRE1α)pathways. Furthermore, the IFN-γ and IL-1β treatment enhanced ER stress-mediated cell death and upregulated the pro-inflammatory cytokine gene expression in Wfs1-KO INS-1 832/13 cells. To confirm these findings, we investigated whether inflammation occurs in a mouse model of Wolfram syndrome. Compared to wild-type mice, 10-month-old whole body Wfs1-KO mouse islets showed a significantly higher density of Iba1, which is a marker for macrophage expression. The islet-infiltrated macrophages in these Wfs1-KO mice expressed the M1-macrophage marker (CD68). There was also strong fibrosis and a high density of endothelial cell marker (CD31) in the Wfs1-KO mouse islets. These results demonstrate that WFS1 loss-of-function enhances the inflammatory responses in pancreatic β-cells. The results in our study identified sterile inflammation as a new pathological mechanism in the development of diabetes in Wolfram syndrome. In Wolfram syndrome model mice, islets are highly infiltrated with macrophages, suggesting that the vicious cycle of ER stress and sterile inflammation accelerates the progression of diabetes in a cell-autonomous and cell-nonautonomous manner. A deeper understanding of the pathophysiology of Wolfram syndrome is essential for developing novel therapeutic targets for the disease. Presentation: No date and time listed

A Novel Missense WFS1 Variant: Expanding the Mutational Spectrum Associated with Nonsyndromic Low-Frequency Sensorineural Hearing Loss.

Background Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) is an uncommon form of hearing loss (HL) that typically affects frequencies at 2000 Hz and below. Heterozygous variants in the WFS1 gene at the DFNA6/14/38 locus are considered a common cause of LFSNHL. To date, 34 different pathogenic genetic variants have been reported to cause LFSNHL with seven of these variants identified in the Chinese population. However, limited reports are available on the association between WFS1 gene and LFSNHL. Here, we report a five-generation Chinese family with an autosomal dominant inheritance pattern of postlingual and progressive LFSNHL. Methods Routine clinical and audiological examinations were performed on 16 affected and 7 healthy members in this family. The targeted next-generation sequencing of 127 known deafness genes was performed to identify variants in affected individuals. Sanger sequencing were further employed to confirm the pathogenic variant identified. Results A novel heterozygous pathogenic genetic variant c.2530G > T (p.Ala844Ser) was identified in the WFS1 gene in all patients of this family. The mutated Ala residue is evolutionarily conserved and cosegregated with HL. The variant was predicted to be deleterious by MutationTaster, PolyPhen-2, LRT, and Fathmm software. Conservation analysis and 3D protein structure model indicated that the variant caused a structural change in the protein. Conclusions Our present study identifies a novel heterozygous WFS1 variant associated with LFSNHL in a Chinese family.

Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome.

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.

β-cyclodextrin based nano gene delivery using pharmaceutical applications to treat Wolfram syndrome.

Wolfram syndromeis a rare multisystem autosomal recessive neurodegenerative disorder that affects the brain and central nervous system. Currently, there is no cure or treatment for Wolfram syndrome. Therefore, new techniques are needed to target the loss of the WFS1 gene. Gene therapy approach to introduce a functional gene using a viral or a non-viral vector could be a treatment strategy for Wolfram syndrome 1(WS1). Viral vectors have therapeutic benefits and greater efficiency; however, they pose a high health risk. Recently pharmaceutical therapeutic research has developed cell-penetrating non-viral nano molecules that could be used as vectors for gene delivery. Among nonviral vectors, the unique properties of β-cyclodextrin suggest that it can be a promising safe vector for gene delivery.

Genetic spectrum and characteristics of autosomal optic neuropathy in Korean: Use of next-generation sequencing in suspected hereditary optic atrophy.

AimsTo evaluate the clinical characteristics and causative genetic variants in autosomal optic atrophy diagnosed using next-generation sequencing (NGS).MethodsA cohort of 57 unrelated families affected with bilateral optic atrophy were recruited from two university-based tertiary referral hospitals from May 2016 to April 2022. Genetic variants were detected using a target enrichment panel consisting of 429 or 595 genes and known deep intronic variants associated with inherited eye diseases, exome sequencing, or genome sequencing. The results of detailed clinical examinations, disease-causing variants, and clinical diagnoses were analyzed.ResultsAmong the 57 probands, 33 (57.9%) were men, and the median age at genetic testing was 19.1 years (interquartile range, 7.6–42.5 years). We identified 22 likely causative variants in 18 families and corresponding diagnostic yields of 31.6% (95% confidence interval, 21.0–44.5%). The diagnostic rate of NGS was higher in patients with infantile or early childhood onset optic atrophy than in those with late-onset or unknown optic atrophy (18/39, 46.2% vs. 0/18, 0%, P < 0.001). Among the 22 variants, 15 were novel in our cohort. The OPA1 variants (n = 7) were found to be the major genetic causes, followed by the NR2F1 variant (n = 4). The causative variants in PTPN23, TMEM126A, NBAS, and WFS1 genes were identified in 4 probands with a recessive form of optic atrophy.ConclusionsBased on the results of diagnostic NGS for optic atrophy, the causative variant could be detected in 31.6% of patients. Our study also demonstrated that NGS is unlikely to help identify molecular causes in late-onset unexplained optic atrophy.

Maternal stress induced endoplasmic reticulum stress and impaired pancreatic islets’ insulin secretion via glucocorticoid receptor upregulation in adult male rat offspring

Exposure to perinatal (prenatal and/or postnatal) stress is considered as a risk factor for metabolic disorders in later life. Accordingly, this study aimed to investigate the perinatal stress effects on the pancreatic endoplasmic reticulum (ER) stress induction, insulin secretion impairment and WFS1 (wolframin ER transmembrane Glycoprotein, which is involved in ER homeostasis and insulin secretion) expression changes, in rat offspring. According to the dams’ period of exposure to variable stress, their male offspring were divided into, control (CTRL); pre-pregnancy, pregnancy, lactation stress (PPPLS); pre-pregnancy stress (PPS); pregnancy stress (PS); lactation stress (LS); pre-pregnancy, pregnancy stress (PPPS); pregnancy, lactation stress (PLS); pre-pregnancy, lactation stress (PPLS) groups. Offspring pancreases were removed for ER extraction and the assessment of ER stress biomarkers, WFS1 gene DNA methylation, and isolated islets’ insulin secretion. Glucose tolerance was also tested. In the stressed groups, maternal stress significantly increased plasma corticosterone levels. In PPS, PS, and PPPS groups, maternal stress increased Bip (Hsp70; heat shock protein family A member 4), Chop (Ddit3; DNA- damage inducible transcript3), and WFS1 protein levels in pancreatic extracted ER. Moreover, the islets’ insulin secretion and content along with glucose tolerance were impaired in these groups. In PPS, PS, LS and PPPS groups, the pancreatic glucocorticoid receptor (GR) expression increased. Maternal stress did not affect pancreatic WFS1 DNA methylation. Thus, maternal stress, during prenatal period, impaired the islets’ insulin secretion and glucose homeostasis in adult male offspring, possibly through the induction of ER stress and GR expression in the pancreas, in this regard the role of WFS1 protein alteration in pancreatic ER should also be considered.

Genetic and prenatal diagnosis of a Chinese pedigree with autosomal recessive Wolfram syndrome 1 due to compound heterozygous variants of WFS1 gene

To explore the genetic pathogenicity for a Chinese pedigree affected with severe syndromic deafness. High-throughput sequencing was carried out to analyze the 415 genes associated with hereditary deafness in the proband who has hearing loss in association with optic atrophy and hyperglycemia. Candidate variants were verified by Sanger sequencing of the proband, her parents and the fetus. The proband was found to harbor compound heterozygous variants of WFS1 gene, namely c.2389G>A (p.Asp797Asn) and c.2345C>T (p.Pro782Leu), which was known to underlie Wolfram syndrome 1. The proband's parents had normal hearing and were both heterozygous carriers for the above variants. The fetus was found to harbor the same compound heterozygous variants and was predicted to have a high risk. The compound heterozygous variants of c.2389G>A and c.2345C>T of the WFS1 gene probably underlay the pathogenesis of hearing loss in the proband. Above finding has facilitated genetic counseling and prenatal diagnosis for this family.

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome.

Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8–13.9) pg/mL] relative to controls [5.6 (4.5–7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.

Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells.

Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates pancreatic β-cell dysfunction and death in diabetes, the contribution of pancreatic β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1-deficiency enhances the gene expression of pro-inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of Wfs1 whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in pancreatic β-cells. Our results indicate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome. The pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome.

Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles

The protein wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. Mutations in Wfs1 gene cause autosomal recessive disorder Wolfram syndrome (WS). The first symptom of the WS is diabetes mellitus, so accurate diagnosis of the disease as WS is often delayed. In this study we aimed to characterize the role of the Wfs1 deficiency on bioenergetics of muscles. Alterations in the bioenergetic profiles of Wfs1-exon-5-knock-out (Wfs1KO) male rats in comparison with their wild-type male littermates were investigated using high-resolution respirometry, and enzyme activity measurements. The changes were followed in oxidative (cardiac and soleus) and glycolytic (rectus femoris and gastrocnemius) muscles. There were substrate-dependent alterations in the oxygen consumption rate in Wfs1KO rat muscles. In soleus muscle, decrease in respiration rate was significant in all the followed pathways. The relatively small alterations in muscle during development of WS, such as increased mitochondrial content and/or increase in the OxPhos-related enzymatic activity could be an adaptive response to changes in the metabolic environment. The significant decrease in the OxPhos capacity is substrate dependent indicating metabolic inflexibility when multiple substrates are available.

Wolfram Syndrome 1: From Genetics to Therapy.

Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the WFS1 gene located on chromosome 4p16 that encodes a transmembrane protein named wolframin. Many studies have shown that wolframin regulates some mechanisms of ER calcium homeostasis and therefore plays a role in cellular apoptosis. More than 200 mutations are responsible for WS1. However, abnormal phenotypes of WS with or without DM, inherited in an autosomal dominant mode and associated with one or more WFS1 mutations, have been found. Furthermore, recessive Wolfram-like disease without DM has been described. The prognosis of WS1 is poor, and the death occurs prematurely. Although there are no therapies that can slow or stop WS1, a careful clinical monitoring can help patients during the rapid progression of the disease, thus improving their quality of life. In this review, we describe natural history and etiology of WS1 and suggest criteria for a most pertinent approach to the diagnosis and clinical follow up. We also describe the hallmarks of new therapies for WS1.

EP264: Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development.

Abstract 114: WFS1 gene associated diabetes phenotypes and identification of a novel founder mutation in Southern India

Background: Wolfram Syndrome (WFS) is a rare, autosomal recessive, progressive disorder characterized by childhood-onset diabetes mellitus (DM), diabetes insipidus, optic atrophy, and sensorineural hearing loss (DIDMOAD). The confirmed early diagnosis of WFS is challenging due to the progressive nature of the disease and WFS1 rare heterozygous variants reported in young-onset DM, the need for comprehensive genetic screening for the early diagnosis of WFS and to characterize the phenotypic spectrum associated with diabetes mellitus.Aims and Objectives: To screen a comprehensive panel of seventeen monogenic diabetes genes in patients with DM, with a clinical suspicion of WFS/non autoimmune T1DM/Young onset DM patients who were tested negative for a MODY panel.Results: Fourteen patients positive for WFS1 variants identified by Next-generation sequencing. Ten patients were positive for homozygous WFS1 mutations, which includes a novel founder mutation WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370SerfsTer173) in three families from south India. We have also identified rare heterozygous WFS1 variants in four patients with young onset diabetes.Conclusion: These findings project the need for NGS-based parallel multigene testing for early diagnosis of WFS and to identify heterozygous WFS1 variants implicated in young onset DM.

PPARG, TMEM163, UBE2E2, and WFS1 Gene Polymorphisms Are Not Significant Risk Factors for Gestational Diabetes in the Polish Population.

Gestational diabetes mellitus (GDM) is a common disorder that occurs in pregnant women, leading to many maternal and neonatal complications. The pathogenesis of GDM is complex and includes risk factors, such as: age, obesity, and family history of diabetes. Studies have shown that genetic factors also play a role in the pathogenesis of GDM. The present study investigated whether polymorphisms in the PPARG (rs1801282), TMEM163 (rs6723108 and rs998451), UBE2E2 (rs6780569), and WFS1 (rs4689388) genes are risk factors for the development of GDM and whether they affect selected clinical parameters in women with GDM. This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) at 24–28 weeks gestation, according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. There were no statistically significant differences in the distribution of polymorphisms studied between women with GDM and pregnant women with normal carbohydrate tolerance, which suggests that these polymorphisms are not risk factors for GDM. We also examined the associations between studied gene polymorphisms and clinical parameters: fasting glucose, daily insulin requirement, body mass before pregnancy, body mass at birth, body mass increase during pregnancy, BMI before pregnancy, BMI at birth, BMI increase during pregnancy, new-born body mass, and APGAR score in women with GDM. We observed lower BMI values before pregnancy and at birth in women with PPARG rs17036160 TT genotype. The results of this study suggest that the PPARG (rs1801282), TMEM163 (rs6723108 and rs998451), UBE2E2 (rs6780569), and WFS1 (rs4689388) gene polymorphisms are not significant risk factors for GDM development in the Polish population and do not affect the clinical parameters in women with GDM; only rs1801282 of the PPARG gene may influence BMI values in women with GDM.

WFS1 Gene–associated Diabetes Phenotypes and Identification of a Founder Mutation in Southern India

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. 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. 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. 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. 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.

Ophthalmologic Microvascular changes in Wolfram syndrome

AbstractPurposeTo evaluate ophthalmic, systemic, genotype features and microvascular abnormalities of patients with Wolfram syndrome (WFS).MethodsCross‐sectional, prospective evaluation of consecutive patients with WFS and healthy subjects. WFS diagnosis was performed based on the clinical presentation and detection of biallelic pathogenic variants in the WFS1 gene. All patients underwent a complete ophthalmological examination and a retinal vasculature evaluation by OCT‐A. Quantitative analysis included: whole‐image vessel density (VD, %), inside disk VD and peripapillary VD of the ONH and peripapillary region, as well as, whole VD for parafoveal superficial capillary plexus (SCP) of the macula.ResultsFifty‐eight eyes were included in this study, 26 eyes from patients with WFS and 32 eyes from healthy subjects. Seven families were included, twelve patients had biallelic pathogenic variants whereas one had one pathogenic variant in the WFS1 gene confirming the diagnosis of WFS type 1 and Wolfram‐like syndrome, respectively. Optic atrophy and diabetes mellitus were the most common systemic findings. The best corrected visual acuity (BCVA) ranged from light perception to 0.1 logMar. Quantitative evaluation demonstrated a significant difference between WFS and healthy subjects on whole‐image VD, inside disk VD, and peripapillary VD (p &lt; 0.001 for all) and SCP perfusion density (p &lt; 0.001). Ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL) thickness have significant decrease in WFS patients with BCVA more than 1 logMar compared to those with less than 1 logMar (p &lt; 0.001 and p = 0.024, respectively).ConclusionsWFS patients had a decreased of vessel density in ONH, peripapillary microvasculature and in macular microvascular networks. Microvasculature changes seem to occur before a severe decrease in visual acuity, and the decreased of the GCC and RNFL thickness.

Interaction between rs6446482 polymorphisms in the WFS1 gene in type 2 diabetes patients

BackgroundType 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. MethodsOne 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. ResultsThis case-control study compared T2DM patients to healthy controls. Age, weight, BMI, FBG, HDL-c, TC, TGs, and family history (p < 0.05). The effect of the rs6446482 polymorphism was performed with PCR-RFLP analysis, and the study results confirmed the positive association with HWE (p = 0.01), genotypes (GG vs. CC: OR-3.29 [95% CI: 1.33–8.13]; p = 0.007), dominance (CC vs. CG + GG: OR-2.12 [95% CI: 1.24–3.92]; p = 0.006), and allele frequencies (G vs. C: OR-2.15 [95% CI: 1.37–3.38]; p = 0.0007), revealing a positive association. ANOVA results showed a negative association between the rs6446482 polymorphism and T2DM risk parameters such as age, weight, height, BMI and FBG. ConclusionThe results of this study confirmed that the rs6446482 polymorphism is associated with T2DM in the Saudi population. This study recommends updating the meta-analysis studies in T2DM with the rs6446482 polymorphism and should also be performed in different modes of diabetes.

Reduced Corneal Sensitivity With Neuronal Degeneration is a Novel Clinical Feature in Wolfram Syndrome

To evaluate corneal sensitivity and corneal nerve morphology among patients with Wolfram syndrome (WFS). An observational clinical case series with confirmatory experiments. We included a group of 12 patients with biallelic mutations in the WFS1 gene and a control group composed of 30 individuals with type 1 diabetes (T1D). All participants (n=42) underwent a complete ophthalmic examination, esthesiometry, and retinal nerve fiber layer assessment using optical coherence tomography. Morphologic assessment of corneal neuropathy by in vivo corneal confocal microscopy was conducted in 11 patients with WFS (both eyes) and 1 WFS patient (1 eye) as well as in 24 patients with T1D (both eyes in 6 patients and 1 eye in 18 patients). Additionally, corneas from Wfs1KO mice and their wild-type littermates were subjected to laser scanning confocal microscopy. Corneal sensitivity was significantly reduced in patients with WFS compared with patients with T1D (4.50 cm [interquartile range, 3.50-5.50 cm] vs 6.00 cm [interquartile range, 6.00-6.00 cm]; P < 10-5). Additionally, corneal nerve fiber and branch density as well as nerve fiber length were low among patients with WFS. Corneal sensitivity correlated with macular average thickness (R=0.6928; P=.039) and best-corrected visual acuity (R=-0.61; P=.002) in the WFS group. Similarly, Wfs1 knockout mice also presented corneal neurodegeneration changes when corneal nerve fiber density and length were measured using laser scanning confocal microscopy. Decreased corneal sensitivity and corneal nerve degeneration are observed in WFS. Corneal sensitivity is linked with the degree of disease progression as measured by visual acuity and retinal thinning.

Variable Expressivity of Wolfram Syndrome in a Family with Multiple Affected Subjects.

PurposeTo study the genetic basis and clinical manifestations of Wolfram syndrome in a multi-affected family.MethodsComplete clinical examinations including urological, ophthalmic, neurological, and endocrinologic assessment were performed for three affected family members. Genomic DNA was extracted from peripheral blood leukocytes with salting out method and all WFS1 exons and their flanking regions were sequenced. Candidate variation was screened for segregation in the pedigree by Sanger sequencing.ResultsA known pathogenic missense mutation in WFS1 gene (c.1885CT which leads to p.Arg629Trp in the encoded protein) was identified in all affected individuals. Both clinical and genetic investigations confirmed Wolfram syndrome diagnosis with variable phenotypic featuresConclusion Identical mutations in the Wolfram syndrome causative gene can lead to variable manifestations of the syndrome even in the same family. Although the medical findings and clinical examination are imperative for the diagnosis of Wolfram syndrome, genetic testing is useful to confirm the diagnosis, especially in cases with possible reduced penetrance of the characteristic signs.