title: Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.
abstract: Autosomal-inherited progressive external ophthalmoplegia (PEO) is an adult-onset disease characterized by the accumulation of multiple mitochondrial DNA (mtDNA) deletions in post-mitotic tissues. Mutations in six different genes have been described to cause the autosomal dominant form of the disease, but only mutations in the DNA polymerase gamma gene are known to cause autosomal recessive PEO (arPEO), leaving the genetic background of arPEO mostly unknown. Here we used whole-exome sequencing and identified compound heterozygous mutations, leading to two amino acid alterations R225W and a novel T230A in thymidine kinase 2 (TK2) in arPEO patients. TK2 is an enzyme of the mitochondrial nucleotide salvage pathway and its loss-of-function mutations have previously been shown to underlie the early-infantile myopathic form of mtDNA depletion syndrome (MDS). Our TK2 activity measurements of patient fibroblasts and mutant recombinant proteins show that the combination of the identified arPEO variants, R225W and T230A, leads to a significant reduction in TK2 activity, consistent with the late-onset phenotype, whereas homozygosity for R225W, previously associated with MDS, leads to near-total loss of activity. Our finding identifies a new genetic cause of arPEO with multiple mtDNA deletions. Furthermore, MDS and multiple mtDNA deletion disorders are manifestations of the same pathogenic pathways affecting mtDNA replication and repair, indicating that MDS-associated genes should be studied when searching for genetic background of PEO disorders.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki 00290, Finland. henna.tyynismaa@helsinki.fi
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
authors.forename: Sofia
authors.initials: S
authors.lastname: Ahola-Erkkilä
authors.forename: Henrikki
authors.initials: H
authors.lastname: Almusa
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pöyhönen
authors.forename: Mari
authors.initials: M
authors.lastname: Korpela
authors.forename: Jari
authors.initials: J
authors.lastname: Honkaniemi
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology*; D008969:Molecular Sequence Data; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000201:enzymology* / Q000235:genetics; D016415:Sequence Alignment; D017384:Sequence Deletion; D013937:Thymidine Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C105339:thymidine kinase 2; D013937:Thymidine Kinase