scholarly journals Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome

2009 ◽  
Vol 160 (2) ◽  
pp. 309-316 ◽  
Author(s):  
Maria Regina R Gasparin ◽  
Felipe Crispim ◽  
Sílvia L Paula ◽  
Maria Beatriz S Freire ◽  
Ivaldir S Dalbosco ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Neurodegenerative Disorder ◽  
Major Gene ◽  
Wolfram Syndrome ◽  
Mild Phenotype ◽  
Homozygous Missense Mutation ◽  
Onset Of Diabetes ◽  
Chromosome 4P16 ◽  
Wfs1 Gene ◽  
Design And Methods

ObjectiveWolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype–phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with WS and to examine the phenotype–genotype relationships in these patients.Design and methodsClinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with WS from 19 families.ResultsWe identified 15 different mutations in the WFS1 gene in 26 patients, among which nine are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although we did not find any clear phenotype–genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea.ConclusionsOur data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype–genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5.

A novel nonsense mutation in the WFS1 gene causes the Wolfram syndrome

2016 ◽  
Vol 29 (5) ◽  
Author(s):  
Shahab Noorian ◽  
Shahram Savad ◽  
Davood Shah Mohammadi
Keyword(s):  
Nonsense Mutation ◽  
Autosomal Recessive ◽  
Neurodegenerative Disorder ◽  
Wolfram Syndrome ◽  
Wfs1 Gene

AbstractWolfram syndrome is a rare autosomal recessive neurodegenerative disorder, which is mostly caused by mutations in the

scholarly journals Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation

2021 ◽  
Author(s):  
Eleonora Panfili ◽  
Giada Mondanelli ◽  
Ciriana Orabona ◽  
Maria L Belladonna ◽  
Marco Gargaro ◽  
...  
Keyword(s):  
Er Stress ◽  
Mononuclear Cells ◽  
Autosomal Recessive Disorder ◽  
Wolfram Syndrome ◽  
Therapeutic Interventions ◽  
T Helper 17 ◽  
Gene Encoding ◽  
Peripheral Blood Mononuclear ◽  
Inflammatory State ◽  
Wfs1 Gene

Abstract Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G > A (in intron 3) and c.757A > T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband’s PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS.

Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings

2012 ◽  
Vol 36 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Tobias B. Haack ◽  
Boris Rolinski ◽  
Birgit Haberberger ◽  
Franz Zimmermann ◽  
Jessica Schum ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Mitochondrial Dysfunctions ◽  
Homozygous Missense Mutation

scholarly journals First description of phosphofructokinase deficiency in spain: identification of a novel homozygous missense mutation in the PFKM gene

2013 ◽  
Vol 4 ◽  
Author(s):  
Joan-Lluis Vives-Corrons ◽  
Pavla Koralkova ◽  
Josep M. Grau ◽  
Maria del Mar Mañú Pereira ◽  
Richard Van Wijk
Keyword(s):  
Missense Mutation ◽  
Homozygous Missense Mutation ◽  
Phosphofructokinase Deficiency

scholarly journals Atypical pyridoxine dependent epilepsy resulting from a new homozygous missense mutation, in ALDH7A1

Seizure ◽  
2018 ◽  
Vol 57 ◽  
pp. 32-33 ◽  
Author(s):  
Zahraa Haidar ◽  
Nadine Jalkh ◽  
Sandra Corbani ◽  
Ali Fawaz ◽  
Eliane Chouery ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Homozygous Missense Mutation

scholarly journals ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia

2018 ◽  
Vol 4 (2) ◽  
pp. e223 ◽  
Author(s):  
Christian G. Bouwkamp ◽  
Zaid Afawi ◽  
Aviva Fattal-Valevski ◽  
Inge E. Krabbendam ◽  
Stefano Rivetti ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Hereditary Spastic Paraplegia ◽  
Krebs Cycle ◽  
Spastic Paraplegia ◽  
Homozygous Carrier ◽  
Clinical Genetic ◽  
Homozygous Missense Mutation ◽  
Recessive Mutations ◽  
Mitochondrial Aconitase ◽  
Essential Enzyme

ObjectiveTo identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP).MethodsClinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP.ResultsA homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia.ConclusionsOur findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

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