دورية أكاديمية
أعرض في EDS

A novel complex neurological phenotype due to a homozygous mutation in FDX2.

التفاصيل البيبلوغرافية
العنوان: A novel complex neurological phenotype due to a homozygous mutation in FDX2.
المؤلفون: Gurgel-Giannetti J; Department of Paediatrics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., Lynch DS; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.; Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, London, UK., Paiva ARB; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Lucato LT; Neuroradiology Section, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Yamamoto G; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Thomsen C; Department of Pathology and Genetics, Sahlgrenska University Hospital, University of Gothenburg, Sweden., Basu S; Institute for Cytobiology and Cytopathology, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35032 Marburg, Germany., Freua F; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Giannetti AV; Department of Surgery, Federal University of Minas Gerais, Belo Horizonte, Brazil., de Assis BDR; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Ribeiro MDO; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Barcelos I; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Sayão Souza K; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Monti F; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Melo US; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Amorim S; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil., Silva LGL; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Macedo-Souza LI; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Vianna-Morgante AM; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Hirano M; Department of Neurology, Columbia University Medical Center, New York, USA., Van der Knaap MS; Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands., Lill R; Institute for Cytobiology and Cytopathology, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35032 Marburg, Germany.; LOEWE Center for Synthetic Microbiology, SynMikro, Hans-Meerwein-Strasse, 35043 Marburg, Germany., Vainzof M; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Oldfors A; Department of Pathology and Genetics, Sahlgrenska University Hospital, University of Gothenburg, Sweden., Houlden H; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.; Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, London, UK., Kok F; Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil.; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
المصدر: Brain : a journal of neurology [Brain] 2018 Aug 01; Vol. 141 (8), pp. 2289-2298.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Oxford University Press
Original Publication: London.
مواضيع طبية MeSH: Ferredoxins/*genetics , Ferredoxins/*physiology, Adolescent ; Adult ; Brazil ; Child ; Electron Transport Complex IV/metabolism ; Female ; Homozygote ; Humans ; Iron/metabolism ; Iron-Sulfur Proteins/genetics ; Iron-Sulfur Proteins/physiology ; Leukoencephalopathies/metabolism ; Male ; Mitochondria/metabolism ; Mitochondrial Proteins/genetics ; Muscular Diseases/genetics ; Myalgia/genetics ; Optic Atrophy/genetics ; Pedigree ; Phenotype ; Succinate Dehydrogenase/metabolism ; Syndrome ; Exome Sequencing
مستخلص: 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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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; United Kingdom MRC_ Medical Research Council
المشرفين على المادة: 0 (Ferredoxins)
0 (Iron-Sulfur Proteins)
0 (Mitochondrial Proteins)
E1UOL152H7 (Iron)
EC 1.3.99.1 (Succinate Dehydrogenase)
EC 1.9.3.1 (Electron Transport Complex IV)
تواريخ الأحداث: Date Created: 20180717 Date Completed: 20190715 Latest Revision: 20240216
رمز التحديث: 20240216
مُعرف محوري في PubMed: PMC6061701
DOI: 10.1093/brain/awy172
PMID: 30010796
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2156
DOI:10.1093/brain/awy172