Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia.
Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include POLG1, the gene encoding the catalytic subunit of mtDNA polymerase (pol gamma), POLG2 encoding its accessory subunit, ANT1 coding the adenine nucleotide translocator and PEO1 which codes for Twinkle, the mitochondrial helicase. Finally OPA1 missense mutations are involved in phenotypes presenting optic atrophy as a major feature.To define the relative contribution of POLG1, POLG2, ANT1 and PEO1 genes to the mtDNA multiple deletion syndromes, we analysed them in a cohort of 67 probands showing accumulation of multiple mtDNA deletions in muscle. The patients were predominantly affected with a mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO). Genetic analysis revealed that 1) PEO1 has a major role in determining familial PEO, since it accounts for 26.8% of familial cases, followed by ANT1 (14.6%) and POLG1 (9.8%); 2) no mutations in any of the known genes were found in 53.7% of probands of this series. Six novel missense mutations contributing to the mutational load of PEO1 gene (p.R334P, p.W315S, p. S426N, p.W474S, p.F478I, p.E479K) were associated with an adult onset PEO phenotype.
Virgilio
Roberta
R
Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, Fondazione I.R.C.C.S. Ospedale Maggiore, Policlinico, Mangiagolli e Regina Elena, Via Sforza 35, 20122, Milano, Italy.
Ronchi
Dario
D
Hadjigeorgiou
Georgios M
GM
Bordoni
Andreina
A
Saladino
Francesca
F
Moggio
Maurizio
M
Adobbati
Laura
L
Kafetsouli
Demetra
D
Tsironi
Evangelia
E
Previtali
Stefano
S
Papadimitriou
Alexandros
A
Bresolin
Nereo
N
Comi
Giacomo P
GP
D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
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