Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay.
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.
Naïmi
Mourad
M
Department of Medical Genetics, Archet 2 Hospital, CHU Nice, France.
Bannwarth
Sylvie
S
Procaccio
Vincent
V
Pouget
Jean
J
Desnuelle
Claude
C
Pellissier
Jean-François
JF
Rötig
Agnes
A
Munnich
Arnold
A
Calvas
Patrick
P
Richelme
Christian
C
Jonveaux
Philippe
P
Castelnovo
Giovanni
G
Simon
Mariella
M
Simon
Melvin
M
Clanet
Michel
M
Wallace
Douglas
D
Paquis-Flucklinger
Véronique
V
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
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