Mutations in (which encodes Wolframin, WFS1) and (which encodes CDGSH iron sulfur domain 2) result in Wolfram syndrome (WS), a rare genetic disorder that starts with juvenile diabetes and progresses to neurological dysfunction. WFS1 and CISD2 belong to different protein families with distinct properties. Despite differences between WFS1 and CISD2, loss-of-function mutations in these proteins result in similar disease phenotypes, suggesting that they have convergent roles. WFS1 and CISD2 both localize at the endoplasmic reticulum (ER), the main intracellular calcium (Ca) store, which is implicated in several diseases, including WS. Here, we not only review the roles of WFS1 and CISD2 in Ca signaling modulation but also point out knowledge gaps. Because WFS1 and CISD2 form complexes with Ca transporters and Ca channels, it is thought that they influence the activity of these transport systems in cells. Together, the studies reviewed here provide a better understanding of the pathogenesis and the severe disease burden of WS and may contribute to the development of therapeutics.
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Insights from a Wolfram syndrome cohort: clinical and molecular findings from a specialized diabetes reference center.
Arch Endocrinol Metab
October 2024
Universidade Estadual de Campinas Faculdade de Ciências Médicas e Hospital de Clínicas Departamento de Pediatria CampinasSP Brasil Departamento de Pediatria, Faculdade de Ciências Médicas e Hospital de Clínicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.
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 molecular analysis.
ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
Nat Commun
July 2024
Departments of Pharmacology and Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia.
Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca handling compromises mitochondrial function and affects neuronal health.
View Article and Find Full Text PDFGenomics of Wolfram Syndrome 1 (WFS1).
Biomolecules
September 2023
Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA 6009, Australia.
Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000-30,000 people are affected by WFS worldwide, and, on average, patients suffering from WFS die at 30 years of age, usually from central respiratory failure caused by massive brain atrophy.
View Article and Find Full Text PDFNeuro-Ophthalmologic Variability in Presentation of Genetically Confirmed Wolfram Syndrome: A Case Series and Review.
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Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Wolfram syndrome is a neurodegenerative disorder caused by pathogenic variants in the genes or . Clinically, the classic phenotype is composed of optic atrophy, diabetes mellitus type 1, diabetes insipidus, and deafness. Wolfram syndrome, however, is phenotypically heterogenous with variable clinical manifestations and age of onset.
View Article and Find Full Text PDFClinical management and obstetric outcome in WFS1 Wolfram syndrome spectrum disorder: A case report and literature review.
Taiwan J Obstet Gynecol
May 2023
Department of Obstetrics and Gynecology, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address:
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.
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