title: Co-occurrence of four nucleotide changes associated with an adult mitochondrial ataxia phenotype.
abstract: BACKGROUND
  Mitochondrial DNA maintenance disorders are an important cause of hereditary ataxia syndrome, and the majority are associated with mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (DNA polymerase gamma), POLG. Mutations resulting in the amino acid substitutions A467T and W748S are the most common genetic causes of inherited cerebellar ataxia in Europe.
  
  
  METHODS
  We report here a POLG mutational screening in a family with a mitochondrial ataxia phenotype. To evaluate the likely pathogenicity of each of the identified changes, a 3D structural analysis of the PolG protein was carried out, using the Alpers mutation clustering tool reported previously.
  
  
  RESULTS
  Three novel nucleotide changes and the p.Q1236H polymorphism have been identified in the affected members of the pedigree. Computational analysis suggests that the p.K601E mutation is likely the major contributing factor to the pathogenic phenotype.
  
  
  CONCLUSIONS
  Computational analysis of the PolG protein suggests that the p.K601E mutation is likely the most significant contributing factor to a pathogenic phenotype. However, the co-occurrence of multiple POLG alleles may be necessary in the development an adult-onset mitochondrial ataxia phenotype.
authors.forename: Ramón
authors.initials: R
authors.lastname: Zabalza
authors.forename: Anssi
authors.initials: A
authors.lastname: Nurminen
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Kaguni
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), Madrid, Spain. egallardo@iib.uam.es.
authors.forename: M Esther
authors.initials: ME
authors.lastname: Gallardo
authors.forename: Belén
authors.initials: B
authors.lastname: Bornstein
mesh_terms: D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human