Mitochondrial DNA depletion and dGK gene mutations

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.

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

“…A minority of affected individuals present initially in infancy or childhood with isolated hepatic disease, occasionally following a viral illness. Affected individuals with this form may develop mild hypotonia and renal involvement manifesting as proteinuria and aminoaciduria [2,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. More recently, DGUOK mutations have been reported in a neonate with clinical and autopsy findings consistent with neonatal hemochromatosis and mtDNA depletion [56], and in individuals with adult-onset mitochondrial myopathy and mtDNA multiple deletions in skeletal muscle [57].…”

Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase

“…Patients with DGUOK deficiency typically present with liver dysfunction at birth, with or without neurological impairment, and most die within the first year of life due to liver failure (Freisinger, et al, 2006;Labarthe, et al, 2005;Salviati, et al, 2002). Early liver transplant appears to be effective in patients with isolated liver involvement (Freisinger, et al, 2006;Labarthe, et al, 2005).…”

Mutation analysis in 16 patients with mtDNA depletion

“…Mutations in the mitochondrial deoxyguanosine kinase (DGUOK [MIM# 601465]) Salviati et al, 2002;Taanman et al, 2002), and in the mitochondrial deoxythymidine kinase genes (TK2 [MIM# 188250]) Mancuso et al, 2002) have been associated with the hepatocerebral and the myopathic forms of MDS in different populations. Both genes are part of the mitochondrial deoxyribonucleotide (dNTPs) salvage pathway.…”