Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletion

• Autosomal-inherited progressive external ophthalmoplegia (PEO) is an adult-onset disease characterized bytheaccumulation ofmultiple mitochondrial DNA(mtDNA) deletionsin post-mitotictissues.Mutations in six dif-ferent genes have been described to cause the autosomal dominant form of the disease, but only mutations inthe DNA polymerase gamma gene are known to cause autosomal recessive PEO (arPEO), leaving the geneticbackground of arPEO mostly unknown. Here we used whole-exome sequencing and identified compound het-erozygous mutations, leading to two amino acid alterations R225W and a novel T230A in thymidine kinase 2(TK2)inarPEOpatients.TK2isanenzymeofthemitochondrialnucleotidesalvagepathwayanditsloss-of-func-tion mutations have previously been shown to underlie the early-infantile myopathic form of mtDNA depletionsyndrome (MDS).Our TK2 activity measurementsof patient fibroblastsand mutant recombinant proteinsshowthat the combination of the identified arPEO variants, R225W and T230A, leads to a significant reduction in TK2activity, consistent with the late-onset phenotype, whereas homozygosity for R225W, previously associatedwith MDS, leads to near-total loss of activity. Our finding identifies a new genetic cause of arPEO with multiplemtDNA deletions. Furthermore, MDS and multiple mtDNA deletion disorders are manifestations of the samepathogenic pathways affecting mtDNA replication andrepair, indicating that MDS-associated genes shouldbe studied when searching for genetic background of PEO disorders.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Genetik (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Genetics (hsv//eng)

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