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Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Gerald Pfeffer, Gráinne S Gorman, Helen Griffin, Marzena Kurzawa-Akanbi, Emma L. Blakely, Ian Wilson, Kamil Sitarz, David Moore, Julie L. Murphy, Charlotte L. Alston, Angela Pyle, Jon Coxhead, Brendan Payne, George H. Gorrie, Cheryl Longman, Marios Hadjivassiliou, John McConville, David Dick, Ibrahim Imam, David Hilton, Fiona Norwood, Mark R. Baker, Stephan R. Jaiser, Patrick Yu-Wai-Man, Michael Farrell, Allan McCarthy, Timothy Lynch, Robert McFarland, Andrew M. Schaefer, Douglass M. Turnbull, Rita Horvath, Robert W. Taylor, Patrick F. Chinnery
DOI: http://dx.doi.org/10.1093/brain/awu060 1323-1336 First published online: 10 April 2014


Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.

  • chronic progressive external ophthalmoplegia
  • hereditary spastic paraplegia
  • paraplegin
  • mtDNA maintenance
  • SPG7
  • Abbreviations
    cytochrome c oxidase
    progressive external ophthalmoplegia
    succinate dehydrogenase
  • This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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