Mitochondrial DNA polymerase γ mutations: An ever expanding molecular and clinical spectrum

Sha Tang, Jing Wang, Ni Chung Lee, Margherita Milone, Michelle C. Halberg, Eric S. Schmitt, William J. Craigen, Wei Zhang, Lee Jun C Wong

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)669-681
Number of pages13
JournalJournal of Medical Genetics
Volume48
Issue number10
DOIs
StatePublished - Oct 2011

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DNA-Directed DNA Polymerase
Mitochondrial DNA
Mutation
Mitochondrial Diseases
Alleles
Chronic Progressive External Ophthalmoplegia
Genes
Comparative Genomic Hybridization
Muscular Diseases
Missense Mutation
Ataxia
Oligonucleotide Array Sequence Analysis
Sequence Analysis
Exons
Milk
Seizures
Age Groups
Amino Acids
DNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mitochondrial DNA polymerase γ mutations : An ever expanding molecular and clinical spectrum. / Tang, Sha; Wang, Jing; Lee, Ni Chung; Milone, Margherita; Halberg, Michelle C.; Schmitt, Eric S.; Craigen, William J.; Zhang, Wei; Wong, Lee Jun C.

In: Journal of Medical Genetics, Vol. 48, No. 10, 10.2011, p. 669-681.

Research output: Contribution to journalArticle

Tang, S, Wang, J, Lee, NC, Milone, M, Halberg, MC, Schmitt, ES, Craigen, WJ, Zhang, W & Wong, LJC 2011, 'Mitochondrial DNA polymerase γ mutations: An ever expanding molecular and clinical spectrum', Journal of Medical Genetics, vol. 48, no. 10, pp. 669-681. https://doi.org/10.1136/jmedgenet-2011-100222
Tang, Sha ; Wang, Jing ; Lee, Ni Chung ; Milone, Margherita ; Halberg, Michelle C. ; Schmitt, Eric S. ; Craigen, William J. ; Zhang, Wei ; Wong, Lee Jun C. / Mitochondrial DNA polymerase γ mutations : An ever expanding molecular and clinical spectrum. In: Journal of Medical Genetics. 2011 ; Vol. 48, No. 10. pp. 669-681.
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