title: A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.
abstract: Autosomal-dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder that is characterized by accumulation of multiple mitochondrial DNA (mtDNA) deletions in postmitotic tissues. The disorder is heterogeneous, with five known nuclear disease genes that encode the proteins ANT1, Twinkle, POLG, POLG2, and OPA1. Defects in these proteins affect mtDNA maintenance, probably leading to stalled replication forks, consequent mtDNA deletion formation, and progressive respiratory chain deficiency. Here we present a large adPEO family with multiple mtDNA deletions, whose disease was not explained by mutations in any of the known adPEO loci. We mapped the disease locus in this family to chromosome 8q22.1-q23.3. The critical linkage region contained the RRM2B gene, which encodes the small subunit of the ribonucleotide reductase p53R2, which has previously been shown to be essential for the maintenance of mtDNA copy number. Mutation screening of RRM2B revealed a heterozygous nonsense mutation in exon 9 (c.979C-->T [p.R327X]) in all affected individuals that was absent in 380 control chromosomes. The same mutation was found to segregate in another adPEO family. The mutant mRNA escaped nonsense-mediated decay and resulted in a protein with truncation of 25 highly conserved C-terminal amino acids essential for the interaction with the ribonucleotide reductase subunit R1. We conclude that dominant-negative or gain-of-function mutations in RRM2B are a cause of multiple mtDNA deletions and adPEO.
authors: Research Program of Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. henna.tyynismaa@helsinki.fi
authors: Henna
authors: H
authors: Tyynismaa
authors: Emil
authors: E
authors: Ylikallio
authors: Mehul
authors: M
authors: Patel
authors: Maria J
authors: MJ
authors: Molnar
authors: Ronald G
authors: RG
authors: Haller
authors: Anu
authors: A
authors: Suomalainen
mesh_terms: D001706:Biopsy; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D008040:Genetic Linkage; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008126:Lod Score; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000601:surgery; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017354:Point Mutation; D012264:Ribonucleotide Reductases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV