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<p>Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as <i>COX6A1</i>, are associated with neuromuscular disorders. While recessive <i>COX6A1</i> variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous <i>COX6A1</i> variant (NM_004373.4: c.329 A &gt; T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (<i>p</i> &lt; 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic <i>COX6A1</i> variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first <i>COX6A1</i> stop-loss variant, and our findings expand the phenotypic and genetic spectrum of <i>COX6A1</i>-related disorders.</p>

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A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction

  • 期刊论文

  • 发表日期：

    2025年10月3日

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  • Qianyun Cai,
  • Haijiao Wang,
  • Rong Luo,
  • Xiao Qian,
  • Zhongjie Zhou

摘要

Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first COX6A1 stop-loss variant, and our findings expand the phenotypic and genetic spectrum of COX6A1-related disorders.