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.

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Other, less common, presentations include spinal muscular atrophylike presentation [13] and chronic progressive external ophthalmoplegia with proximal muscle weakness [23]. Milder presentations have been reported and include late onset proximal muscle weakness [15], adult-onset progressive myopathy [22], and sensorineural hearing loss [21].…”

“…mtDNA content is typically severely reduced in muscle tissue. Electron transport chain (ETC) activity assays in skeletal muscle typically show decreased activity of multiple complexes with complex I, I + III, and IV being the most affected [13][14][15][16][17][18][19][20][21][22][23].…”

TK2 mutation presenting as indolent myopathy

“…[1][2][3] However, the progression of weakness may vary, 4 as shown by recently described adult patients with late-onset myopathy. 5,6 To date, only 5 adult patients with TK2-related MDS have been reported. Herein, we describe a man who had several unusual features.…”

Oxidative Stress Induced S-glutathionylation and Proteolytic Degradation of Mitochondrial Thymidine Kinase 2

“…Deficiency in TK2 activity is associated with the devastating mitochondrial DNA depletion syndrome, and the disease phenotype extends to the involvement of multiple organs beside skeletal muscle, as described in initial reports (1)(2)(3)(4)(5). TK2 is expressed in all tissues at low levels; however, little is known regarding TK2 regulation at the transcriptional, translational, and post-translational levels.…”