Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs

Brain, vol. 146, pp. 4191–4199

Abstract

COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary CoQ10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder. We identified COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy with upper neuron involvement, expending the clinical phenotype associated with defects in this gene. A recurrent p.Met1? change was identified in five families from Brazil with evidence of a founder effect. Fibroblasts isolated from patients revealed a substantial depletion of COQ7 protein levels, indicating protein instability leading to loss of enzyme function. High-performance liquid chromatography assay showed that fibroblasts from patients had reduced levels of CoQ10, and abnormal accumulation of the biosynthetic precursor DMQ10. Accordingly, fibroblasts from patients displayed significantly decreased oxygen consumption rates in patients, suggesting mitochondrial respiration deficiency. Induced pluripotent stem cell-derived motor neurons from patient fibroblasts showed significantly increased levels of extracellular neurofilament light protein, indicating axonal degeneration. Our findings indicate a molecular pathway involving CoQ10 biosynthesis deficiency and mitochondrial dysfunction in patients with distal hereditary motor neuropathy. Further studies will be important to evaluate the potential benefits of CoQ10 supplementation in the clinical outcome of the disease.

Authors 24

1. Adriana P. Rebelo

   University of Miami · Dr. John T. Macdonald Foundation

   Affiliation as printed

   Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA

2. Pedro José Tomaselli

   Universidade de São Paulo

   Affiliation as printed

   Department of Neurology, University of São Paulo , Ribeirão Preto, 14048-900 , Brazil

3. Jessica Medina

   University of Miami · Dr. John T. Macdonald Foundation

   Affiliation as printed

   Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA

4. Ying Wang

   McGill University

   Affiliation as printed

   Department of Biology, McGill University , Montreal, QC, H3A 1A1 , Canada

5. Maike Franziska Dohrn Aachen Department of Neurology, Medical Faculty

   RWTH Aachen University · University of Miami · Dr. John T. Macdonald Foundation

   Affiliation as printed

   Department of Neurology, Medical Faculty, RWTH Aachen University , Aachen 52074 , Germany

   Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA

6. Eva Nývltová

   University of Miami

   Affiliation as printed

   Department of Neurology, University of Miami Miller School of Medicine , Miami, FL 33136 , USA

7. Matt Christopher Danzi

   University of Miami · Dr. John T. Macdonald Foundation

   Affiliation as printed

   Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA

8. Sean E Smith

   Washington University in St. Louis

   Affiliation as printed

   Department of Neurology, Washington University , St. Louis, MO 63112 , USA

9. Alan Pestronk

   Washington University in St. Louis

   Affiliation as printed

   Department of Neurology, Washington University , St. Louis, MO 63112 , USA

10. Chengcheng Li

    Washington University in St. Louis

    Affiliation as printed

    Department of Neurology, Washington University , St. Louis, MO 63112 , USA

11. Elizabeth H. Jacobs

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA

12. Shawna M. E. Feely

    University of Iowa

    Affiliation as printed

    Department of Neurology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242 , USA

13. Marcondes C. França

    Universidade de São Paulo

    Affiliation as printed

    Department of Neurology, University of São Paulo , Ribeirão Preto, 14048-900 , Brazil

14. Marcus Vinicius Gomes

    Universidade de São Paulo

    Affiliation as printed

    Department of Neurology, University of São Paulo , Ribeirão Preto, 14048-900 , Brazil

15. Diogo Fernandes dos Santos

    Universidade Federal de Uberlândia

    Affiliation as printed

    Department of Neurology, Federal University of Uberlândia , Uberlândia, MG 38405-320 , Brazil

16. Surinder Kumar

    University of Miami · Sylvester Comprehensive Cancer Center

    Affiliation as printed

    Department of Pathology & Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine , Miami, FL 33136 , USA

17. David B. Lombard

    University of Miami · Sylvester Comprehensive Cancer Center

    Affiliation as printed

    Department of Pathology & Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine , Miami, FL 33136 , USA

18. Mario Saporta

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA

19. Siegfried Hekimi

    McGill University

    Affiliation as printed

    Department of Biology, McGill University , Montreal, QC, H3A 1A1 , Canada

20. Antoni Barrientos

    University of Miami

    Affiliation as printed

    Department of Neurology, University of Miami Miller School of Medicine , Miami, FL 33136 , USA

21. Conrad Chris Weihl

    Washington University in St. Louis

    Affiliation as printed

    Department of Neurology, Washington University , St. Louis, MO 63112 , USA

22. Michael E. Shy

    University of Iowa

    Affiliation as printed

    Department of Neurology, Carver College of Medicine, University of Iowa , Iowa City, IA 52242 , USA

23. Wilson Marques

    Universidade de São Paulo

    Affiliation as printed

    Department of Neurology, University of São Paulo , Ribeirão Preto, 14048-900 , Brazil

24. Stephan L. Zuchner corresponding

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami , Miller School of Medicine, Miami, FL 33136 , USA