A new pathogenic POLG variant

Abstract

POLG gene mutations are the most common causes of inherited mitochondrial disorders. The enzyme produced by this gene is responsible for the replication and repair of mitochondrial DNA. To date, around 300 pathogenic variants have been described in this gene. The resulting clinical outcomes of POLG mutations are widely variable in both phenotype and severity. There is considerable overlap in the phenotype of the so-called POLG syndromes with no clear genotype-phenotype correlation. Here we describe a newly discovered pathogenic variant in the POLG gene in a 7-year-old male that died of uncontrollable refractory status epilepticus. Genetic epilepsy panel sequencing identified two variants in the POLG gene, the common p.A467T pathological mutation and a novel p.S809R POLG variant found in trans with the p.A467T POLG that accompanied a severely reduced mitochondrial DNA level in the patient's tissues.

Keywords: Alpers-Huttenlocher syndrome; DNA polymerase gamma; Mitochondria; Mitochondrial depletion; POLG syndrome.

Fig. 1

Conservation of POLG amino acid sequence from across eukaryotes. Yellow highlighted amino acids are invariant across all POLG sequences, while blue highlighted amino acids are conserved in animal POLG sequences. The Ser809 residue is depicted by the arrow.

Fig. 2

(A) Three-dimensional structural examination of the Ser809 residue in the Pol g heterotrimer structure. Fig. 2B. The heterotrimer structure with DNA bound in the active site. Blue and purple polypeptides represent the p55 accessory subunit. The p140 catalytic subunit is colored in black (exonuclease domain), and red, blue, green and yellow according to color scheme of Lee et al. (https://pubmed.ncbi.nlm.nih.gov/19837034/). Fig. 2C. Close up view of the Ser809 residue positioned between the two thumb domain helices. Fig. 2D. Alteration to Arg and possible steric hinderance. Images were generated with Pymol using PDB: 4ZTU (https://pubmed.ncbi.nlm.nih.gov/26056153/).