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  • Nikkanen, Joni; Landoni, Juan Cruz; Balboa, Diego; Haugas, Maarja; Partanen, Juha; Paetau, Anders; Isohanni, Pirjo; Brilhante, Virginia; Suomalainen, Anu (2018)
    DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS-specific enhancers that drive expression specifically in oculomotor complex and sensory interneurons of the spinal cord, completely overlapping with the regions showing neuronal death in POLG patients. The regulatory locus also expresses two functional RNAs, LINC00925-RNA and MIR9-3, which are coexpressed with POLG. The MIR9-3 targets include NR2E1, a transcription factor maintaining neural stem cells in undifferentiated state, and MTHFD2, the regulatory enzyme of mitochondrial folate cycle, linking POLG expression to stem cell differentiation and folate metabolism. Our evidence suggests that distant genomic non-coding regions contribute to regulation of genes encoding mitochondrial proteins. Such genomic arrangement of POLG locus, driving expression to CNS regions affected in POLG patients, presents a potential mechanism for CNS-specific manifestations in POLG disease.
  • Pohjoismaki, Jaakko L. O.; Goffart, Steffi; Taylor, Robert W.; Turnbull, Douglas M.; Suomalainen, Anu; Jacobs, Howard T.; Karhunen, Pekka J. (2010)
  • Khan, Nahid A.; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J.; Auwerx, Johan; Suomalainen, Anu (2014)
  • Vartiainen, Suvi; Chen, Shanjun; George, Jack; Tuomela, Tea; Luoto, Kaisa R.; O'Dell, Kevin M. C.; Jacobs, Howard T. (2014)
  • Thompson, Kyle; Majd, Homa; Dallabona, Christina; Reinson, Karit; King, Martin S.; Alston, Charlotte L.; He, Langping; Lodi, Tiziana; Jones, Simon A.; Fattal-Valevski, Aviva; Fraenkel, Nitay D.; Saada, Ann; Haham, Alon; Isohanni, Pirjo; Vara, Roshni; Barbosa, Ines A.; Simpson, Michael A.; Deshpande, Charu; Puusepp, Sanna; Bonnen, Penelope E.; Rodenburg, Richard J.; Suomalainen, Anu; Ounap, Katrin; Elpeleg, Orly; Ferrero, Ileana; McFarland, Robert; Kunji, Edmund R. S.; Taylor, Robert W. (2016)
    Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondria' respiratory chain deficiencies associated with a marked loss of mitochondria' DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondria' DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondria' DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondria' disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease.