Search

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.

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

Introduction: 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., Methods: 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., Results: 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., Discussion: 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., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The most adverse perinatal outcome of intrahepatic cholestasis of pregnancy (ICP) is sudden fetal death related to acute fetoplacental hypoxia. Corticotrophin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) proteins may have a compensatory response to hypoxic stress., Methods: A total of 108 singleton pregnant women were divided into three groups: control, late-onset ICP, and early-onset ICP. Enzyme-linked immunosorbent assays were used to detected maternal serum CRH, UCN, and WFS1 levels. Western blotting and real-time polymerase chain reaction were conducted to quantify placental protein and mRNA levels of CRH, UCN, and WFS1. Pearson correlation scatterplots and Pearson correlation matrix were employed to testify the correlation., Results: Placental WFS1 had a positive relation with placental UCN (r = 0.69, P < 0.05) and serum UCN (r = 0.36, P < 0.05). Placental CRH was positively correlated with maternal serum CRH (r = 0.53, P < 0.05). Maternal serum and placental levels of CRH, UCN, and WFS1 significantly increased in the early-onset ICP group compared with the control group (P < 0.05). Placental levels of UCN and WFS1 in the early-onset ICP group were significantly elevated and higher in comparison with the late-onset ICP group (P < 0.05). However, the transcriptional levels of CRH, UCN, and WFS1 were impaired in the early-onset ICP group., Discussion: Our study revealed that transcription and translation of WFS1, CRH, and UCN were altered during pregnancies complicated by early-onset ICP. This disrupted compensatory response mediated by WFS1 and CRH family peptides in early-onset ICP may play a significant role in the pathogenesis of sudden fetal death in acute fetal hypoxia., (Copyright © 2019. Published by Elsevier Ltd.)

Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder characterized by the presentation of early onset type I diabetes mellitus and optic atrophy with later onset diabetes insipidus and deafness. WFS1 gene was identified on chromosome 4p16.1 as the gene responsible for WS disease given that most of the WS patients were found to carry mutations in this gene. This study was carried out to investigate the molecular spectrum of WFS1 gene in Jordanian families. Molecular and clinical characterization was performed on five WS patients from two unrelated Jordanian families. Our data indicated that WS patients of the first family harbored two deletion mutations (V415del and F247fs) located in exon 8 and exon 7 respectively, with a compound heterozygous pattern of inheritance; while in the second family, we identified a novel nonsense mutation (W185X) located in exon 5 in the N-terminal cytoplasmic domain with a homozygous pattern of inheritance. This mutation can be considered as loss of function mutation since the resulting truncated protein lost both the transmembrane domain and the C-terminal domain. Additionally, the W185X mutation lies within the CaM binding domain in wolframin protein which is thought to have a role in the regulation of wolframin function in response to calcium levels.

Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)