Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database

BBA Clin. 2017 Apr 18;7:147-156. doi: 10.1016/j.bbacli.2017.04.001. eCollection 2017 Jun.


DNA polymerase gamma (POLG) is the replicative polymerase responsible for maintaining mitochondrial DNA (mtDNA). Disorders related to its functionality are a major cause of mitochondrial disease. The clinical spectrum of POLG syndromes includes Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), the ataxia neuropathy spectrum (ANS) and progressive external ophthalmoplegia (PEO). We have collected all publicly available POLG-related patient data and analyzed it using our pathogenic clustering model to provide a new research and clinical tool in the form of an online server. The server evaluates the pathogenicity of both previously reported and novel mutations. There are currently 176 unique point mutations reported and found in mitochondrial patients in the gene encoding the catalytic subunit of POLG, POLG. The mutations are distributed nearly uniformly along the length of the primary amino acid sequence of the gene. Our analysis shows that most of the mutations are recessive, and that the reported dominant mutations cluster within the polymerase active site in the tertiary structure of the POLG enzyme. The POLG Pathogenicity Prediction Server ( is targeted at clinicians and scientists studying POLG disorders, and aims to provide the most current available information regarding the pathogenicity of POLG mutations.

Keywords: AHS, Alpers-Huttenlocher syndrome; ANS, Ataxia neuropathy spectrum; DNA polymerase gamma; IP, Intrinsic processivity subdomain of POLGA spacer-domain; MCHS, Childhood myocerebrohepatopathy spectrum; MEMSA, Myoclonic epilepsy myopathy sensory ataxia; Mitochondrial disorder; Mutation database; PDB ID, Four-character identification code for a protein structure in the RSCB PDB database; PEO, Progressive external ophthalmoplegia; PNF, Putatively non-functional enzyme; POLG syndrome; POLG, DNA polymerase gamma; POLGA, Catalytic subunit of DNA polymerase gamma; POLGB, Accessory subunit of DNA polymerase gamma; Pathogenicity prediction; Patient database; SNP, Single nucleotide polymorphism/non-pathogenic mutation.