Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.
OBJECTIVE
Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically and genetically heterogeneous group of autosomal recessive diseases characterized by a reduction in mtDNA copy number. Several nuclear genes have been shown to account for these severe oxidative phosphorylation disorders, but the disease-causing mutations remain largely unknown.


METHODS
By virtue of homozygosity mapping, we tested candidate genes involved in mtDNA maintenance in patients born to consanguineous parents.


RESULTS
We found homozygosity for microsatellite markers flanking the PEO1 gene, encoding the mitochondrial Twinkle helicase, in two sibs presenting a hepatocerebral form of MDS. Sequencing the PEO1 gene showed a homozygous mutation at a conserved position of the protein in the two patients (T457I). The modeling of the Twinkle protein showed that T457 is located in the interface between two monomers of the hexameric enzyme. Finally, using purified recombinant protein, we demonstrated that the T457I mutant Twinkle has a defective helicase activity.


CONCLUSIONS
Although dominant Twinkle mutations have been previously reported in patients with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions, we report here the first recessive Twinkle mutation in patients with hepatocerebral form of MDS. Identifying other Twinkle mutations in MDS and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on the isolated proteins should help in understanding why some mutations are recessive and others are dominant.
Sarzi
Emmanuelle
E
Institut National de la Sante et de la Recherche Médicale U781 and Service de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
Goffart
Steffi
S
Serre
Valérie
V
Chrétien
Dominique
D
Slama
Abdelhamid
A
Munnich
Arnold
A
Spelbrink
Johannes N
JN
Rötig
Agnès
A
D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D004265:DNA Helicases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors*; D018628:Gene Dosage; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism; D018895:Microsatellite Repeats; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation; D035781:Siblings; D013577:Syndrome
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human