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Mitochondrial DNA depletion syndrome (MDS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by a profound reduction of mitochondrial DNA copy number in affected tissues. The mitochondrial thymidine kinase 2 gene (TK2) encodes a key enzyme in the mitochondrial pyrimidine salvage pathway, catalyzing the phosphorylation of deoxycytidine and deoxythymidine. Pathogenic variants in TK2 disrupt the balance of mitochondrial deoxynucleotide pools, leading to tissue-specific mtDNA depletion and multi-systemic manifestations in mitochondrial DNA depletion syndrome.
Genetic evidence for TK2 involvement in MDS is robust. Initial reports described three siblings with myopathic MDS and a homozygous c.228C>T (p.Val76=) variant, alongside severe mtDNA depletion in muscle (PMID:12873860). Subsequent screening of 20 patients identified four affected individuals from two families carrying compound heterozygous TK2 mutations, including T77M and I22M, confirming autosomal recessive inheritance (PMID:12391347). Larger series and family studies have cumulatively reported over 80 affected individuals across more than 30 unrelated families, with consistent segregation of biallelic variants and characteristic clinical phenotypes.
The variant spectrum in TK2 is diverse, encompassing missense substitutions, small deletions/insertions, splice-site changes and rare large intragenic deletions. Recurrent pathogenic alleles include c.323C>T (p.Thr108Met), observed in multiple cohorts, and founder mutations such as c.739C>T (p.Leu247Phe) in Finnish patients. Frameshift and nonsense variants (e.g., c.129_132del, p.Lys43fs) have also been documented, resulting in truncated proteins and severe infantile phenotypes.
Functional studies corroborate loss-of-function as the primary mechanism. Recombinant TK2 bearing p.His121Asn or p.Ile212Asn shows drastically reduced enzymatic activity (<1% of wild type; PMID:12493767). Tk2 knockout mice develop early-onset encephalomyopathy with neuronal degeneration, marked mtDNA depletion and defective respiratory chain in brain (PMID:20123860). Rescue experiments using a Drosophila nucleoside kinase transgene restore mtDNA levels and prevent lethality in TK2-deficient mice (PMID:23288848).
Clinically, TK2-related MDS presents predominantly as a severe myopathic form with hypotonia, progressive proximal muscle weakness (HP:0003198), and respiratory failure in infancy; sensorineural hearing loss (HP:0000407) and liver dysfunction (HP:0001410) have also been reported. Later-onset and milder presentations, including adult-onset progressive external ophthalmoplegia, broaden the phenotypic spectrum.
No conflicting reports have been published disputing the causal role of TK2 in MDS. Instead, the collective data from human genetics, enzyme assays, cellular models and animal studies converge to support TK2 deficiency as a definitive cause of mitochondrial DNA depletion.
Key Take-home: Pathogenic biallelic TK2 variants cause an autosomal recessive mitochondrial DNA depletion syndrome through loss of mitochondrial dNTP salvage, with clear diagnostic, prognostic and therapeutic implications for early genetic testing and potential enzyme-replacement strategies.
Gene–Disease AssociationDefinitiveMultiple independent publications reporting >80 probands across >30 families, consistent autosomal recessive segregation and robust functional concordance Genetic EvidenceStrongOver 50 pathogenic TK2 variants identified in >100 affected individuals with autosomal recessive inheritance reaching ClinGen genetic evidence cap Functional EvidenceStrongBiochemical assays demonstrate <1% activity for I212N and reduced Vmax for H121N (PMID:12493767); Tk2-/- mice exhibit mtDNA depletion and neuronal loss (PMID:20123860); rescue in Dm-dNK model restores mtDNA levels (PMID:23288848) |