title: Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay.
abstract: ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.
authors.affiliation: Department of Medical Genetics, Archet 2 Hospital, CHU Nice, France.
authors.forename: Mourad
authors.initials: M
authors.lastname: Naïmi
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bannwarth
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pellissier
authors.forename: Agnes
authors.initials: A
authors.lastname: Rötig
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.forename: Christian
authors.initials: C
authors.lastname: Richelme
authors.forename: Philippe
authors.initials: P
authors.lastname: Jonveaux
authors.forename: Giovanni
authors.initials: G
authors.lastname: Castelnovo
authors.forename: Mariella
authors.initials: M
authors.lastname: Simon
authors.forename: Melvin
authors.initials: M
authors.lastname: Simon
authors.forename: Michel
authors.initials: M
authors.lastname: Clanet
authors.forename: Douglas
authors.initials: D
authors.lastname: Wallace
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004265:DNA Helicases / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D010375:Pedigree; D011110:Polymorphism, Genetic; D017384:Sequence Deletion
chemical_list: D033741:Adenine Nucleotide Translocator 1; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D004265:DNA Helicases; C431576:TWNK protein, human