DGUOK – Mitochondrial DNA Depletion Syndrome 3 (Hepatocerebral Type)

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) is an autosomal recessive disorder characterized by early-onset hepatic failure and lactic acidosis caused by biallelic mutations in DGUOK (PMID:37456661). The disease is particularly frequent in the Middle East and North Africa, where diagnostic delays occur due to non-specific cerebro-hepatic deterioration.

Genetic evidence includes a Lebanese founder nonsense variant c.235C>T (p.Gln79Ter) in homozygous state and multiple additional truncating, missense, splice-site, and frameshift alleles reported across consanguineous families from seven countries (PMID:37456661; PMID:17073823; PMID:19900589). Inheritance is autosomal recessive with confirmed homozygosity or compound heterozygosity in affected individuals.

Segregation analysis in consanguineous pedigrees demonstrated co-segregation of biallelic DGUOK variants with disease in at least two affected siblings (PMID:19900589).

Functional assays reveal severely reduced kinase activity (14% residual for N46S/L266R) with impaired ATP binding in mutant mitochondria (PMID:17073823), and in vitro supplementation of dAMP/dGMP in DGUOK-deficient myotubes partially restores mtDNA copy number (PMID:19221117).

An F180S mouse model manifests altered mitochondrial function, increased Ucp1 expression in adipose tissue, and metabolic changes recapitulating aspects of human DGUOK deficiency, providing an in vivo system for pathomechanistic and therapeutic studies (PMID:36709400).

No studies have refuted the association between DGUOK and mitochondrial DNA depletion syndrome 3. The integration of multiple unrelated probands, familial segregation, concordant in vitro and in vivo functional data supports a strong gene–disease relationship.

Key Take-home: Biallelic DGUOK mutations, including a Lebanese founder c.235C>T (p.Gln79Ter), cause autosomal recessive hepatocerebral mtDNA depletion syndrome, with robust genetic and functional evidence guiding diagnosis, genetic counseling, and consideration of nucleoside-based therapies.

References

• Unspecified Journal • 2024 • Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene. PMID:37456661
• The Biochemical Journal • 2007 • Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion. PMID:17073823
• Mitochondrion • 2010 • A novel c.592-4_c.592-3delTT mutation in DGUOK gene causes exon skipping. PMID:19900589
• Human Molecular Genetics • 2009 • In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA levels in mitochondrial depletion syndromes. PMID:19221117
• International Journal of Obesity • 2023 • Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice. PMID:36709400

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