, Volume 16, Issue 1, pp 1–9 | Cite as

Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy

  • Senda Ajroud-Driss
  • Faisal Fecto
  • Kaouther Ajroud
  • Irfan Lalani
  • Sarah E. Calvo
  • Vamsi K. Mootha
  • Han-Xiang Deng
  • Nailah Siddique
  • Albert J. Tahmoush
  • Terry D. Heiman-Patterson
  • Teepu Siddique
Original Article


Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5 % of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.


Mitochondrial myopathy Genetics CHCHD10 Mitochondria 



We thank the patients and their family members for participating in this study. We also thank Kreshnik B. Ahmeti, LiJun Cheng, and Yi Yang for their technical assistance. This work was supported by the National Institute of Neurological Disorders and Stroke (NS050641); the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship; the David C. Asselin MD Memorial Fund; the Vena E. Schaff ALS Research Fund; the George Link, Jr. Foundation; and the Foglia Family Foundation. This work was supported by a grant (R01GM097136) from the National Institutes of Health to VKM. Imaging work was performed at the Northwestern University Cell Imaging Facility generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.

Conflict of interest


Supplementary material

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Supplementary Table 2 (DOCX 18 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Senda Ajroud-Driss
    • 1
  • Faisal Fecto
    • 1
  • Kaouther Ajroud
    • 1
  • Irfan Lalani
    • 1
  • Sarah E. Calvo
    • 4
    • 5
    • 6
    • 7
  • Vamsi K. Mootha
    • 4
    • 5
    • 6
    • 7
  • Han-Xiang Deng
    • 1
  • Nailah Siddique
    • 1
  • Albert J. Tahmoush
    • 8
    • 9
  • Terry D. Heiman-Patterson
    • 8
    • 10
  • Teepu Siddique
    • 1
    • 2
    • 3
  1. 1.Division of Neuromuscular Medicine, The Ken and Ruth Davee Department of Neurology and Clinical Neurosciences, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Interdepartmental Neuroscience ProgramNorthwestern UniversityChicagoUSA
  3. 3.Department of Cell and Molecular Biology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  4. 4.Howard Hughes Medical InstituteChevy ChaseUSA
  5. 5.Department of Molecular BiologyMassachusetts General HospitalBostonUSA
  6. 6.Department of Systems BiologyHarvard Medical SchoolBostonUSA
  7. 7.Broad InstituteCambridgeUSA
  8. 8.Department of NeurologyThomas Jefferson UniversityPhiladelphiaUSA
  9. 9.APG NeurologyAtlantiCare Physician GroupEgg Harbor TownshipUSA
  10. 10.Department of Neurology, College of MedicineDrexel UniversityPhiladelphiaUSA

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