Journal article
Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs
Brain (London, England : 1878), Vol.146(10), pp.4191-4199
10/03/2023
DOI: 10.1093/brain/awad158
PMCID: PMC10545612
PMID: 37170631
Abstract
Rebelo et al. identify COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy with upper motor neuron involvement, thereby expanding the clinical phenotype associated with defects in this gene.
COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ(10)) biosynthesis in mitochondria. CoQ(10) 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 CoQ(10) 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 CoQ(10), and abnormal accumulation of the biosynthetic precursor DMQ(10). 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 CoQ(10) biosynthesis deficiency and mitochondrial dysfunction in patients with distal hereditary motor neuropathy. Further studies will be important to evaluate the potential benefits of CoQ(10) supplementation in the clinical outcome of the disease.
Details
- Title: Subtitle
- Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs
- Creators
- Adriana P. Rebelo - Univ Miami, Dr John T Macdonald Fdn, Miller Sch Med, Dept Human Genet, Miami, FL 33136 USAPedro J. Tomaselli - Universidade de São PauloJessica Medina - University of MiamiYing Wang - McGill UniversityMaike F. Dohrn - RWTH Aachen UniversityEva Nyvltova - University of MiamiMatt C. Danzi - Univ Miami, Dr John T Macdonald Fdn, Miller Sch Med, Dept Human Genet, Miami, FL 33136 USAMark Garrett - Washington University in St. LouisSean E. Smith - Washington University in St. LouisAlan Pestronk - Washington Univ, Dept Neurol, St Louis, MO 63112 USAChengcheng Li - Washington University in St. LouisAriel Ruiz - Dr. John T. Macdonald FoundationElizabeth Jacobs - Dr. John T. Macdonald FoundationShawna M. E. Feely - University of IowaMarcondes C. Franca Jr - Universidade de São PauloMarcus Gomes - Universidade de São PauloDiogo F. Santos - Univ Fed Uberlandia, Dept Neurol, BR-38405320 Uberlandia, MG, BrazilSurinder Kumar - Sylvester Comprehensive Cancer CenterDavid B. Lombard - University of MiamiMario Saporta - University of MiamiSiegfried Hekimi - McGill UniversityAntoni Barrientos - University of MiamiConrad Weihl - Washington Univ, Dept Neurol, St Louis, MO 63112 USAMichael E. Shy - University of Iowa, Iowa Neuroscience InstituteWilson Marques - Universidade de São PauloStephan Zuchner - University of Miami
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.146(10), pp.4191-4199
- DOI
- 10.1093/brain/awad158
- PMID
- 37170631
- PMCID
- PMC10545612
- NLM abbreviation
- Brain
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Publisher
- Oxford Univ Press
- Number of pages
- 9
- Grant note
- DO 2386/1-1 / German Research Foundation (Deutsche Forschungsgemeinschaft, DFG); German Research Foundation (DFG) 5U54NS065712; 5R01NS105755 / NCATS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Muscular Dystrophy Association CMT Association Hereditary Neuropathy Foundation MR/S005021/1 / MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) FDN-159916 / Foundation grant from the Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR)
- Language
- English
- Date published
- 10/03/2023
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984473214402771
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