title: Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.
abstract: 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.
authors.affiliation: 1 Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pfeffer
authors.forename: Gráinne S
authors.initials: GS
authors.lastname: Gorman
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.forename: Marzena
authors.initials: M
authors.lastname: Kurzawa-Akanbi
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Ian
authors.initials: I
authors.lastname: Wilson
authors.forename: Kamil
authors.initials: K
authors.lastname: Sitarz
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.forename: Julie L
authors.initials: JL
authors.lastname: Murphy
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.forename: Jon
authors.initials: J
authors.lastname: Coxhead
authors.forename: Brendan
authors.initials: B
authors.lastname: Payne
authors.forename: George H
authors.initials: GH
authors.lastname: Gorrie
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Marios
authors.initials: M
authors.lastname: Hadjivassiliou
authors.forename: John
authors.initials: J
authors.lastname: McConville
authors.forename: David
authors.initials: D
authors.lastname: Dick
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Imam
authors.forename: David
authors.initials: D
authors.lastname: Hilton
authors.forename: Fiona
authors.initials: F
authors.lastname: Norwood
authors.forename: Mark R
authors.initials: MR
authors.lastname: Baker
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Jaiser
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.forename: Michael
authors.initials: M
authors.lastname: Farrell
authors.forename: Allan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Timothy
authors.initials: T
authors.lastname: Lynch
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schaefer
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000368:Aged; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D019054:Evoked Potentials, Motor / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011930:Reaction Time
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: SPG7; chronic progressive external ophthalmoplegia; hereditary spastic paraplegia; mtDNA maintenance; paraplegin
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