title: Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population.
abstract: BACKGROUND
  Both dominant and recessive mutations were reported in the gene encoding the mitochondrial (mt) DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). Phenotypes other than PEO were recently documented in patients with mutations in the POLG gene.
  
  
  OBJECTIVE
  To screen patients with mitochondrial disease and multiple mtDNA deletions in muscle for mutations in the coding regions of the POLG, PEO1, and SLC25A4 genes.
  
  
  METHODS
  To identify the underlying molecular defect in a group of patients with multiple mtDNA deletions comparing their molecular genetic findings with those of healthy controls.
  
  
  METHODS
  Twenty-four patients (16 men and 8 women) diagnosed with mitochondrial disease and having multiple mtDNA deletions in muscle by Southern blot analysis. Thirteen patients had PEO; 2 had PEO alone, 4 had PEO and myopathy, and 5 had PEO and multisystem involvement. Four patients had multisystem disease without PEO. The remaining 9 patients had isolated myopathy. DNA from 100 healthy individuals was also studied.
  
  
  RESULTS
  No mutation was identified in the PEO1 or SLC25A4 genes. Nine POLG mutations were observed in 6 of 24 patients. Four novel mutations were detected and mapped in the linker region (M603L) and in the pol domain of the enzyme (R853W; D1184N; R1146C). Five patients with PEO had mutations: 2 were compound heterozygotes, 1 was homozygous, and another showed a mutation in a single allele. The remaining patient also showed a sole mutation and had an unusual phenotype lacking ocular involvement.
  
  
  CONCLUSIONS
  POLG molecular defects were found in 25% of our patients with multiple mtDNA deletions and mitochondrial disease. The uncommon phenotype found in 1 of these patients stresses the clinical variability of patients harboring POLG mutations. Molecular studies in the POLG gene should be addressed in patients with mitochondrial disease, particularly in those with PEO, and multiple mtDNA deletions.
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Universidad Autónoma de Madrid, Hospital Universitario 12 de Octubre, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: González-Vioque
authors.forename: Alberto
authors.initials: A
authors.lastname: Blázquez
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernández-Moreira
authors.forename: Belén
authors.initials: B
authors.lastname: Bornstein
authors.forename: Juan
authors.initials: J
authors.lastname: Bautista
authors.forename: Javier
authors.initials: J
authors.lastname: Arpa
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Campos
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Fernández-Moreno
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arenas
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Martín
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D026501:Blotting, Southwestern / Q000379:methods; D004265:DNA Helicases; D000074002:DNA Polymerase gamma; D019915:DNA Primase / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000235:genetics; D024101:Mitochondrial Proteins; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D013030:Spain
chemical_list: D033741:Adenine Nucleotide Translocator 1; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D019915:DNA Primase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D004265:DNA Helicases; C431576:TWNK protein, human