POLG2 – mitochondrial DNA depletion syndrome

A homozygous missense variant in the accessory subunit of mitochondrial DNA polymerase γ, POLG2, has been reported in a 3-month-old boy presenting with fulminant hepatic failure and severe mtDNA depletion in liver and muscle (MONDO:0018158). Whole-exome sequencing revealed a c.544C>T (p.Arg182Trp) variant, predicted to disrupt p55 homodimerization and processive DNA synthesis, consistent with an autosomal recessive inheritance model. Both parents were heterozygous and asymptomatic, with no additional affected relatives, indicating limited familial segregation (PMID:27592148).

Biochemical studies of POLG2 disease variants support a loss-of-function mechanism: certain mutant p55 proteins exhibit reduced stimulation of processivity, decreased binding to the catalytic subunit, impaired dsDNA binding, altered mitochondrial localization, and dominant-negative effects in vitro (PMID:21555342; PMID:26123486). Although p.Arg182Trp has not been biochemically characterized, these concordant functional data for homologous variants substantiate the pathogenic mechanism of impaired mtDNA replication.

Key Take-home: POLG2 homozygous loss-of-function variants cause early-onset mitochondrial DNA depletion syndrome with hepatic failure, informing diagnostic sequencing and genetic counseling.

References

• European Journal of Medical Genetics • 2016 • Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. PMID:27592148
• Human Molecular Genetics • 2011 • Biochemical analysis of human POLG2 variants associated with mitochondrial disease. PMID:21555342
• Human Molecular Genetics • 2015 • POLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity. PMID:26123486

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