A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions

Henna Tyynismaa, Emil Ylikallio, Mehul Patel, Maria J. Molnar, Ronald G. Haller, Anu Suomalainen

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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.

Original languageEnglish (US)
Pages (from-to)290-295
Number of pages6
JournalAmerican Journal of Human Genetics
Volume85
Issue number2
DOIs
StatePublished - Aug 14 2009

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Chronic Progressive External Ophthalmoplegia
Mitochondrial DNA
Mutation
Ribonucleotide Reductases
Chromosomes
Nonsense Mediated mRNA Decay
Maintenance
Mitochondrial Diseases
Proteins
Essential Amino Acids
Nonsense Codon
Electron Transport
Exons
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions. / Tyynismaa, Henna; Ylikallio, Emil; Patel, Mehul; Molnar, Maria J.; Haller, Ronald G.; Suomalainen, Anu.

In: American Journal of Human Genetics, Vol. 85, No. 2, 14.08.2009, p. 290-295.

Research output: Contribution to journalArticle

Tyynismaa, Henna ; Ylikallio, Emil ; Patel, Mehul ; Molnar, Maria J. ; Haller, Ronald G. ; Suomalainen, Anu. / A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions. In: American Journal of Human Genetics. 2009 ; Vol. 85, No. 2. pp. 290-295.
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