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<p>Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is a rare autosomal recessive neuromuscular disorder characterized by childhood onset of progressive muscle weakness and exercise intolerance. It is caused by mutations in the <i>FDX2</i> gene, encoding the mitochondrial protein ferredoxin 2 (FDX2), a central component of the cellular FeS protein biogenesis. To date there are gaps in our understanding of how FDX2 mutations impact mitochondrial pathophysiology in MEOAL patients. In this work we report a multidisciplinary study of a pediatric patient with a diagnosis of neuromuscular disorder, with multiorgan involvement, associated with a novel homozygous mutation in <i>FDX2</i>, i.e., c.200+4 A &gt; G. We found that: (i) the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids; (ii) patient’s cells have low levels of FDX2; (iii) the mutant FDX2 likely retains its functional integrity, as can be inferred by the absence of significant structural or backbone dynamic differences relative to the wild type protein; (iv) cultured patient’s cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation; (v) the levels of the mitochondrial SOD2 are significantly diminished in patient’s cells and may contribute to weak ROS production. Collectively, the results show that the <i>FDX2</i> mutation leads to a severe decrease of FDX2 protein, resulting in a primary mild cellular FeS protein assembly defect and in the secondary consequences mentioned above, that together may explain the pathogenesis of this MEOAL case.</p>

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A novel mutation in FDX2 provides insights into the pathogenesis of MEOAL mitochondrial neuromuscular disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Davide Doni,
  • Deborah Grifagni,
  • Federica Cavion,
  • Bianca Buchignani,
  • Roberta Battini,
  • Elisa Baschiera,
  • Maria Andrea Desbats,
  • Rosa Pasquariello,
  • Giuseppina Covello,
  • Eva De Pascale,
  • Alice Boarolo,
  • Ilaria Cestonaro,
  • Denis Badocco,
  • Paolo Pastore,
  • Geppo Sartori,
  • Oliver Stehling,
  • Roland Lill,
  • Filippo M. Santorelli,
  • Leonardo Salviati,
  • Simone Ciofi-Baffoni,
  • Paola Costantini

摘要

Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is a rare autosomal recessive neuromuscular disorder characterized by childhood onset of progressive muscle weakness and exercise intolerance. It is caused by mutations in the FDX2 gene, encoding the mitochondrial protein ferredoxin 2 (FDX2), a central component of the cellular FeS protein biogenesis. To date there are gaps in our understanding of how FDX2 mutations impact mitochondrial pathophysiology in MEOAL patients. In this work we report a multidisciplinary study of a pediatric patient with a diagnosis of neuromuscular disorder, with multiorgan involvement, associated with a novel homozygous mutation in FDX2, i.e., c.200+4 A > G. We found that: (i) the mutation alters the splicing of the gene transcript, giving rise to a mutant protein in which 19 N-terminal residues encoded by exon 2 are replaced by 21 different amino acids; (ii) patient’s cells have low levels of FDX2; (iii) the mutant FDX2 likely retains its functional integrity, as can be inferred by the absence of significant structural or backbone dynamic differences relative to the wild type protein; (iv) cultured patient’s cells show impaired mitochondrial respiration, defects in many FeS proteins, and enhanced mitochondrial iron accumulation; (v) the levels of the mitochondrial SOD2 are significantly diminished in patient’s cells and may contribute to weak ROS production. Collectively, the results show that the FDX2 mutation leads to a severe decrease of FDX2 protein, resulting in a primary mild cellular FeS protein assembly defect and in the secondary consequences mentioned above, that together may explain the pathogenesis of this MEOAL case.