CMT-POLG

Genetic Context

HGNC-Approved Gene Symbol

POLG

Gene Full Name

DNA polymerase gamma, catalytic subunit

Chromosome

15q26.1

Zygosity of Responsible Variant

Homozygous or Compound Heterozygous

Mitochondrial Involvement

Yes

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
Medium

Prediction:
In CMT-POLG the literature attributes disease to biallelic loss of function: POLG encodes the catalytic subunit of DNA polymerase gamma, the only polymerase that replicates mitochondrial DNA, and recessive alleles such as p.Ala467Thr and p.Trp748Ser leave a hypomorphic enzyme with reduced processivity and impaired coupling to its accessory subunit. Mitochondrial DNA is depleted and accumulates deletions, and the resulting respiratory-chain failure reaches sensory and motor axons alongside the ataxic and epileptic presentations of the POLG spectrum.

Rationale:
Two hypomorphic copies are required because partial polymerase activity is tolerated: p.Ala467Thr heterozygotes are common in northern European populations and healthy. Dominant POLG alleles do exist, clustering in the polymerase domain and causing progressive external ophthalmoplegia by interfering with the wild-type enzyme, a different lesion from these recessive hypomorphs. Residual activity varies widely across recessive genotypes, and the grade of medium follows from that.

ClinVar Pathogenic Variants

View POLG ClinVar Variants

POLG OMIM Entry

POLG OMIM