A novel complex neurological phenotype due to a homozygous mutation in FDX2
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/44411 |
Resumo: | Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis. |
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2022-08-19T17:30:46Z2022-08-19T17:30:46Z20181310.1093/brain/awy1720006-8950http://hdl.handle.net/1843/44411Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.Defeitos na biogênese do cluster ferro-enxofre [Fe-S] são cada vez mais reconhecidos como causadores de doenças neurológicas. Mutações em vários genes que codificam proteínas envolvidas na montagem da proteína mitocondrial [Fe-S] levam a fenótipos neurológicos complexos. Uma classe de proteínas essenciais na montagem inicial do cluster são as ferredoxinas. FDX2 é expresso de forma ubíqua e é essencial na formação de novo de aglomerados de [2Fe-2S] em humanos. Descrevemos e definimos geneticamente uma nova síndrome neurológica complexa identificada em duas famílias brasileiras, com uma nova mutação homozigótica em FDX2. Os pacientes foram avaliados clinicamente, submetidos a ressonância magnética, estudos de condução nervosa, EMG e biópsia muscular. Para definir a etiologia genética, foi realizada uma combinação de mapeamento de homozigose e sequenciamento de todo o exoma. Identificamos seis pacientes de duas famílias aparentemente não aparentadas com herança autossômica recessiva de um fenótipo neurológico complexo envolvendo atrofia óptica e nistagmo desenvolvendo-se aos 3 anos de idade, seguidos de miopatia e episódios recorrentes de cãibras, mialgia e fraqueza muscular na primeira ou segunda década de vida. A neuropatia axonal sensório-motora levou à fraqueza distal progressiva. A ressonância magnética revelou uma leucoencefalopatia reversível ou parcialmente reversível. A biópsia muscular demonstrou um padrão incomum de succinato desidrogenase regional e deficiência de citocromo c oxidase com acúmulo de ferro. O fenótipo foi mapeado em ambas as famílias para a mesma mutação homozigótica missense em FDX2 (c.431C > T, p.P144L). O efeito deletério da mutação foi validado por reação em cadeia da polimerase de transcrição reversa em tempo real e análise de Western blot, que demonstrou expressão normal de mRNA de FDX2, mas expressão severamente reduzida da proteína FDX2 no tecido muscular. Este estudo descreve um novo fenótipo neurológico complexo com características incomuns de ressonância magnética e biópsia muscular, mapeado conclusivamente para uma mutação em FDX2, que codifica uma ferredoxina mitocondrial ubíqua expressa essencial para a biogênese inicial do cluster [Fe-S].engUniversidade Federal de Minas GeraisUFMGBrasilICB - DEPARTAMENTO DE MORFOLOGIAMED - DEPARTAMENTO DE CIRURGIAMED - DEPARTAMENTO DE PEDIATRIABrainFDX2CérebroMúsculoNervoAtrofia ÓpticaA novel complex neurological phenotype due to a homozygous mutation in FDX2Um novo fenótipo neurológico complexo devido a uma mutação homozigótica em FDX2info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://academic.oup.com/brain/article/141/8/2289/5054138?login=falseJuliana Gurgel GiannettiBruno Della Ripa de AssisMara Dell Ospedale RibeiroIsabella BarcelosKatiane Sayão SouzaFernanda MontiUirá Souto MeloSimone AmorimLeonardo SilvaLúcia Inês Macedo-souzaAngela Vianna MorganteDavid LynchMichio HiranoMarjo Van Der KnaapRoland LillMariz VainzofAnders OldforsHenry HouldenFernando KokAnderson Rodrigues Brandão de PaivaLeandro Tavares LucatoGuilherme YamamotoChrister ThomsenSomsuvro BasuFernando FreuaAlexandre Varella Giannettiapplication/pdfinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGLICENSELicense.txtLicense.txttext/plain; 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dc.title.pt_BR.fl_str_mv |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
dc.title.alternative.pt_BR.fl_str_mv |
Um novo fenótipo neurológico complexo devido a uma mutação homozigótica em FDX2 |
title |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
spellingShingle |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 Juliana Gurgel Giannetti FDX2 Cérebro Músculo Nervo Atrofia Óptica |
title_short |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
title_full |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
title_fullStr |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
title_full_unstemmed |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
title_sort |
A novel complex neurological phenotype due to a homozygous mutation in FDX2 |
author |
Juliana Gurgel Giannetti |
author_facet |
Juliana Gurgel Giannetti Bruno Della Ripa de Assis Mara Dell Ospedale Ribeiro Isabella Barcelos Katiane Sayão Souza Fernanda Monti Uirá Souto Melo Simone Amorim Leonardo Silva Lúcia Inês Macedo-souza Angela Vianna Morgante David Lynch Michio Hirano Marjo Van Der Knaap Roland Lill Mariz Vainzof Anders Oldfors Henry Houlden Fernando Kok Anderson Rodrigues Brandão de Paiva Leandro Tavares Lucato Guilherme Yamamoto Christer Thomsen Somsuvro Basu Fernando Freua Alexandre Varella Giannetti |
author_role |
author |
author2 |
Bruno Della Ripa de Assis Mara Dell Ospedale Ribeiro Isabella Barcelos Katiane Sayão Souza Fernanda Monti Uirá Souto Melo Simone Amorim Leonardo Silva Lúcia Inês Macedo-souza Angela Vianna Morgante David Lynch Michio Hirano Marjo Van Der Knaap Roland Lill Mariz Vainzof Anders Oldfors Henry Houlden Fernando Kok Anderson Rodrigues Brandão de Paiva Leandro Tavares Lucato Guilherme Yamamoto Christer Thomsen Somsuvro Basu Fernando Freua Alexandre Varella Giannetti |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Juliana Gurgel Giannetti Bruno Della Ripa de Assis Mara Dell Ospedale Ribeiro Isabella Barcelos Katiane Sayão Souza Fernanda Monti Uirá Souto Melo Simone Amorim Leonardo Silva Lúcia Inês Macedo-souza Angela Vianna Morgante David Lynch Michio Hirano Marjo Van Der Knaap Roland Lill Mariz Vainzof Anders Oldfors Henry Houlden Fernando Kok Anderson Rodrigues Brandão de Paiva Leandro Tavares Lucato Guilherme Yamamoto Christer Thomsen Somsuvro Basu Fernando Freua Alexandre Varella Giannetti |
dc.subject.other.pt_BR.fl_str_mv |
FDX2 Cérebro Músculo Nervo Atrofia Óptica |
topic |
FDX2 Cérebro Músculo Nervo Atrofia Óptica |
description |
Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018 |
dc.date.accessioned.fl_str_mv |
2022-08-19T17:30:46Z |
dc.date.available.fl_str_mv |
2022-08-19T17:30:46Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
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article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1843/44411 |
dc.identifier.doi.pt_BR.fl_str_mv |
10.1093/brain/awy172 |
dc.identifier.issn.pt_BR.fl_str_mv |
0006-8950 |
identifier_str_mv |
10.1093/brain/awy172 0006-8950 |
url |
http://hdl.handle.net/1843/44411 |
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eng |
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eng |
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Brain |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Universidade Federal de Minas Gerais |
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UFMG |
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Brasil |
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ICB - DEPARTAMENTO DE MORFOLOGIA MED - DEPARTAMENTO DE CIRURGIA MED - DEPARTAMENTO DE PEDIATRIA |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
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