A novel heterozygous mutation of the WFS1
 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome

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.

Download Full-text

A Novel Compound Heterozygous Mutation in the WFS1 Gene (C.1997 G>A and C.2113_2114 ins T) Causes wolfram Syndrome: A Case Report

10.21203/rs.3.rs-38184/v1 ◽

2020 ◽

Author(s):

Reyida Aishajiang ◽

Cheng Li ◽

Bo-Tao Shen ◽

Jian Sun ◽

Wei Zhao

Keyword(s):

Case Report ◽

Autosomal Recessive Disorder ◽

Later Life ◽

Wolfram Syndrome ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Sagittal Sinus ◽

Wfs1 Gene ◽

Tract Infections

Abstract Background:Wolfram syndrome (WS) is a rare autosomal recessive disorder associated with early-onset diabetes mellitus (DM), diabetes insipidus (DI), optic atrophy (OA) and hearing impairment. Most patients with WS have mutations in the WFS1 gene, which encodes wolframin. This case report describes a patient with a novel heterozygous mutation of WFS1.Case Presentation:The proband was a 27-year-old Chinese male with WS who had developed DM at the age of 2 years, DI in the first decade, OA, neurogenic bladder and urinary tract infections in the second decade, and neurological abnormalities in later life. Magnetic resonance imaging suggested superior sagittal sinus enlargement and atrophy of the medulla and pons. Sequencing showed that the proband’s asymptomatic parents were both carriers: the father carried a heterozygous c.1997G>A mutation that creates a premature stop at codon 666 (W666X) and that the proband’s asymptomatic mother carried a heterozygous c.2113_2114insT mutation that generates a frameshift downstream to codon 705 (K705Ifs*7) and leads to a stop at codon 711. The proband had both the above C-terminal mutations, resulting in the substitution of N-glycosylation sitesthat are associated with the stability of wolframin.Conclusion:We have identified a novel compound heterozygous mutation of WFS1 that is associated with WS. Our findings may facilitate future screening of WS carriers.

Download Full-text

Defective Endoplasmic Reticulum–Mitochondria Connection Is a Hallmark of Wolfram Syndrome

Contact ◽

10.1177/2515256419847407 ◽

2019 ◽

Vol 2 ◽

pp. 251525641984740 ◽

Cited By ~ 1

Author(s):

Benjamin Delprat ◽

Jennifer Rieusset ◽

Cécile Delettre

Keyword(s):

Endoplasmic Reticulum ◽

Wolfram Syndrome ◽

Membrane Interface ◽

Cellular Functions ◽

Neuronal Calcium Sensor Protein ◽

Calcium Exchange ◽

Apoptosis And Inflammation ◽

Wfs1 Gene ◽

Regulate Lipid Metabolism ◽

Er Membrane

Interactions between endoplasmic reticulum (ER) and mitochondria are key components of essential cellular functions. Indeed, these membrane appositions are necessary for proper Ca2+ transfer from ER to mitochondria, to regulate lipid metabolism, apoptosis, and inflammation. We report that the ER protein WFS1 interacts with the neuronal calcium sensor protein NCS1 to regulate mitochondria associated-ER membrane formation. Mutations in the WFS1 gene are associated with Wolfram syndrome, a rare neurodegenerative disease. We demonstrated that human WFS1-deficient cells lack NCS1 and fail to tether ER and mitochondria, resulting in a decrease in Ca2+ transfer and mitochondrial respiration. Interestingly, we showed that NCS1 overexpression in WFS1-deficient cells restored ER–mitochondria interactions and calcium exchange. Our results suggest that WFS1 regulates ER tethering to mitochondria through NCS1 and that restoration of NCS1 expression could be a therapeutic tool for restoring calcium signaling at the mitochondria associated-ER membrane interface and mitochondrial function in Wolfram syndrome.

Download Full-text

Genetic Predisposition for Type 1 Diabetes Mellitus - The Role of Endoplasmic Reticulum Stress in Human Disease Etiopathogenesis

Journal of Medical Biochemistry ◽

10.2478/v10011-010-0016-9 ◽

2010 ◽

Vol 29 (3) ◽

pp. 139-149 ◽

Cited By ~ 6

Author(s):

Karmen Stankov

Keyword(s):

Diabetes Mellitus ◽

Endoplasmic Reticulum ◽

Type 1 Diabetes ◽

Endoplasmic Reticulum Stress ◽

Type 1 Diabetes Mellitus ◽

Genetic Predisposition ◽

Human Disease ◽

Wolfram Syndrome

Genetic Predisposition for Type 1 Diabetes Mellitus - The Role of Endoplasmic Reticulum Stress in Human Disease EtiopathogenesisThe increasing incidence of diabetes mellitus worldwide has prompted a rapid growth in the pace of scientific discovery of the mechanisms involved in the etiopathogenesis of this multifactorial disease. Accumulating evidence suggests that endoplasmic reticulum stress plays a role in the pathogenesis of diabetes, contributing to pancreatic beta cell loss and insulin resistance. Wolfram syndrome is an autosomal recessive neurodegenerative disorder accompanied by insulin-dependent diabetes mellitus and progressive optic atrophy. The pathogenesis of this rare neurodegenerative genetic disease is unknown. A Wolfram gene (WFS1 locus) has recently been mapped to chromosome 4p16.1, but there is evidence for locus heterogeneity, including the mitochondrial genome deletion. Recent positional cloning led to identification of the second WFS locus, a mutation in the CISD2 gene, which encodes an endoplasmic reticulum intermembrane small protein. Our results were obtained by the analysis of a families belonging to specific population, affected by Wolfram syndrome. We have identified the newly diagnosed genetic alteration of WFS1 locus, a double non-synonymous and frameshift mutation, providing further evidence for the genetic heterogeneity of this syndrome. Newly identified mutations may contribute to the further elucidation of the pathogenesis of Wolfram syndrome, as well as of the complex mechanisms involved in diabetes mellitus development.

Download Full-text