Mitochondrial DNA depletion and dGK gene mutations

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Abstract
Mitochondrial DNA depletion syndrome is a clinically heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. The recent discovery of mutations in the deoxyguanosine kinase (dGK) gene in patients with the hepatocerebral form of mitochondrial DNA depletion syndrome prompted us to screen 21 patients to determine the frequency of dGK mutations, further characterize the clinical spectrum, and correlate genotypes with phenotypes. We detected mutations in three patients (14%). One patient had a homozygous GATT duplication (nucleotides 763–766), and another had a homozygous GT deletion (nucleotides 609–610); both mutations lead to truncated proteins. The third patient was a compound heterozygote for two missense mutations (R142K and E227K) that affect critical residues of the protein. These mutations were associated with variable phenotypes, and their low frequencies suggests that dGK is not the only gene responsible for mitochondrial DNA depletion in liver. The patient with the missense mutations had isolated liver failure and responded well to liver transplantation, which may be a therapeutic option in selected cases.
Funding Information
  • the National Institutes of Health (PO1HD32062, NS11766)
  • Muscular Dystrophy Association
  • National Institutes of Health (NS02235)
  • Irving Clinical Research Career Award
  • Telethon Italia (439b)
  • University of Padova
  • Fondo Investigación Sanitaria (01/0108-02)
  • Fundación Ilundain
  • Gobierno Vasco