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American journal of human genetics. 2025 Jun 3:S0002-9297(25)00188-0. doi: 10.1016/j.ajhg.2025.05.007 Q18.12024

Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome

FASTKD5双等位基因突变与细胞色素c氧化酶缺乏和早发或晚发利什曼病相关性研究 翻译改进

Hana Antonicka  1, Woranontee Weraarpachai  2, Katherine M Szigety  3, Robert Kopajtich  4, James B Gibson  5, Johan L K Van Hove  6, Marisa W Friederich  6, Piervito Lopriore  7, Christiane Neuhofer  8, Roxanne A Van Hove  9, Michel A Cole  10, Richard Reisdorph  10, James T Peterson  11, Katherine J Dempsey  12, Rebecca D Ganetzky  13, Michelangelo Mancuso  7, Holger Prokisch  14, Eric A Shoubridge  15

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作者单位

  • 1 Department of Human Genetics, McGill University, Montreal, QC H3A 2B4, Canada; The Neuro, Montreal Neurological Institute, Montreal, QC H3A 2B4, Canada.
  • 2 Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 3 Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 4 Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum Munich, Neuherberg, Germany; School of Medicine, Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany.
  • 5 Section of Metabolic Genetics, Dell Children's Medical Center of Central Texas, Austin, TX, USA; Department of Pediatrics, Dell Medical School at University of Texas at Austin, Austin, TX, USA.
  • 6 Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA; Mitochondrial Laboratory, Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
  • 7 Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • 8 Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum Munich, Neuherberg, Germany; School of Medicine, Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.
  • 9 Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.
  • 10 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 11 Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 12 Division of Genetics, Department of Pediatrics, Atrium Health Levine Children's Hospital, Charlotte, NC, USA.
  • 13 Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 14 Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum Munich, Neuherberg, Germany; School of Medicine, Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Munich, Munich, Germany.
  • 15 Department of Human Genetics, McGill University, Montreal, QC H3A 2B4, Canada; The Neuro, Montreal Neurological Institute, Montreal, QC H3A 2B4, Canada. Electronic address: eric.shoubridge@mcgill.ca.

    • DOI: 10.1016/j.ajhg.2025.05.007 PMID: 40499538

    摘要 中英对照阅读

    Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.

    Keywords: FASTKD5; Leigh syndrome; RNA processing; cytochrome c oxidase deficiency; mitochondrial DNA; mitochondrial disease; mitochondrial gene expression; mitochondrial translation; neurodegenerative disease.

    Keywords：FASTKD5 mutations; leigh syndrome

    通过外显子组测序，我们在三个患有莱氏综合征（一种以脑干和基底节区病变为主的进行性神经退行性疾病）的患者中鉴定出FASTKD5基因中的复合杂合变异。这些变异为未知意义变异，而FASTKD5编码一个对初级线粒体转录本在非经典切割位点上mRNA加工过程至关重要的线粒体蛋白。在这三个患者中，我们发现了三种错义变异和两种导致提前终止密码子的移码变异。通过对两名患者的成纤维细胞进行分析，发现FASTKD5蛋白的稳定态水平降低、细胞色素c氧化酶亚基1的翻译减少、复合物IV装配受损以及随后的细胞色素c氧化酶酶活性下降。这些缺陷的程度似乎与临床表型的严重程度相关。表达野生型FASTKD5 cDNA（而非错义变异体的cDNAs）可修复患者成纤维细胞的所有分子缺陷，证明了等位基因具有致病性。三个鉴定出的错义突变中，有两个导致几乎完全的功能丧失，而另一个则是由于蛋白质稳定性受损而导致的低度表达。这些与FASTKD5双等位变异相关联的线粒体疾病病例，为由复合物IV缺乏引起的莱氏综合征的一系列原发性遗传突变列表增添了新的内容。

    关键词： FASTKD5; 莱氏综合征; RNA加工; 细胞色素c氧化酶缺乏; 线粒体DNA; 线粒体疾病; 线粒体基因表达; 线粒体翻译; 神经退行性疾病。

    关键词：快速酮酸脱氢酶5突变; 细胞色素c氧化酶缺乏; 利什曼病综合征

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    期刊名：American journal of human genetics

    缩写：AM J HUM GENET

    ISSN：0002-9297

    e-ISSN：1537-6605

    IF/分区：8.1/Q1

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    Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome