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Mitochondrial DNA polymerase γ mutations: an ever expanding molecular and clinical spectrum
  1. Sha Tang1,
  2. Jing Wang1,
  3. Ni-Chung Lee2,
  4. Margherita Milone3,
  5. Michelle C Halberg1,
  6. Eric S Schmitt1,
  7. William J Craigen1,
  8. Wei Zhang1,
  9. Lee-Jun C Wong1
  1. 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  2. 2Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
  3. 3Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Lee-Jun C Wong, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA; ljwong{at}


Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic regions of the POLG gene from 2697 unrelated patients with clinical presentations suggestive of POLG deficiency. Informative mutations have been identified in 136 unrelated individuals (5%), including 92 patients with two recessive pathogenic alleles and three patients harbouring a dominant mutation. Twenty-four novel recessive mutations and a novel possible dominant mutation, p.Y951N, were identified. All missense mutations occurred at evolutionarily conserved amino acids within functionally important regions identified by molecular modelling analyses. Oligonucleotide array comparative genomic hybridisation analyses performed on DNA samples from 81 patients with one mutant POLG allele identified a large intragenic deletion in only one patient, suggesting that large deletions in POLG are rare. The 92 patients with two mutant alleles exhibited a broad spectrum of disease. Almost all patients in all age groups had some degree of neuropathy. Seizures, hepatopathy, and lactic acidaemia were predominant in younger patients. By comparison, patients who developed symptoms in adulthood had a higher percentage of myopathy, sensory ataxia, and chronic progressive external ophthalmoplegia (CPEO)/ptosis. In conclusion, POLG mutations account for a broad clinical spectrum of mitochondrial disorders. Sequence analysis of the POLG gene should be considered as a part of routine screening for mitochondrial disorders, even in the absence of apparent mitochondrial DNA abnormalities.

  • POLG
  • Alpers syndrome
  • mtDNA depletion
  • liver failure
  • mtDNA multiple deletions
  • diagnosis
  • diagnostics tests
  • genetics
  • molecular genetics
  • cardiomyopathy
  • metabolic disorders
  • neuromuscular disease
  • muscle disease

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  • Competing interests None.

  • Patient consent This is a retrospective database mining study and all the information presented in the manuscript is sufficiently anonymised. Patients are identified by numbers only. Other information includes age at onset, clinical phenotype, and mutations detected. There are no pictures of the patients.

  • Ethics approval Institutional Review Board, Baylor College of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.