# Novel biallelic TK2 mutations cause mitochondrial DNA depletion syndrome with infantile early-onset lipid storage myopathy

## TL;DR

A new mutation in the TK2 gene causes mitochondrial DNA depletion syndrome with early-onset muscle disease in infants.

## Contribution

Identifies a novel compound heterozygous mutation in TK2 with a large deletion and confirms its pathogenicity in mitochondrial DNA depletion syndrome.

## Key findings

- The patient had a compound heterozygous mutation in TK2 (E5-E10 del and c.311C > A).
- The deletion mutation reduced TK2 protein and mitochondrial function in HEK293T cells.
- Mitochondrial dysfunction included increased ROS and reduced ATP production.

## Abstract

Mutations in the TK2 gene are strongly associated with mitochondrial DNA depletion syndrome (MDS), a severe condition with high mortality and poor outcomes. Although many MDS cases are reported, those linked to TK2 mutations with lipid deposition are rare. Large deletions in the TK2 gene are even rarer.

We conducted whole-exome sequencing to find the gene linked to MDS, followed by genomic and structural analyses, histopathological, and functional analyses to assess the mutations' pathogenicity. Additionally, a HEK293T cell model with TK2 mutations was created to investigate the impact of large deletions on mitochondrial function.

The patient was found to have a novel compound heterozygous mutation in the TK2 gene, consisting of a large deletion spanning exons 5–10 (E5-E10 del) and a previously reported missense mutation (c.311C > A, p.Arg104His). Analysis of the patient's muscle tissue demonstrated a marked reduction in mtDNA content and a significant impairment in overall mitochondrial function. In the HEK293T cell model, the group with the deletion mutation exhibited a notable reduction in TK2 protein expression and levels of mitochondrial complex subunits when compared to the control group. Furthermore, there was an observed increase in ROS levels, a decrease in ATP production, and compromised mitochondrial respiratory chain function. Moreover, we conducted a comprehensive review of the previously reported genotypic and phenotypic spectrum of TK2 mutations in the literature.

This case report underscores the detrimental impact of large fragment deletion mutations in the TK2 gene and elucidates their role in the pathogenesis of MDS. It broadens the spectrum of known TK2 mutations and enhances our understanding of the structural and functional consequences of these mutations.

The online version contains supplementary material available at 10.1186/s13023-025-03639-x.