POLG

POLG
National Center for Biotechnology Information, U.S. National Library of Medicine · Public domain · source
Name	POLG
Caption	Human mitochondrial DNA polymerase catalytic subunit
Other names	DNA polymerase gamma, DNA Pol γ
Location	Chromosome 15q24
Organism	Homo sapiens

POLG

Introduction

POLG is the nuclear gene encoding the catalytic subunit of human mitochondrial DNA polymerase gamma, a key enzyme for replication and repair of mitochondrial DNA, first characterized in studies linking mitochondrial DNA depletion to human disease, and widely investigated in laboratories including NIH, Wellcome Trust Sanger Institute, Max Planck Society, Harvard Medical School, Stanford University, University of Oxford, Cambridge University, and Cold Spring Harbor Laboratory. Research on POLG has intersected with work by investigators at Massachusetts General Hospital, Johns Hopkins University, Mayo Clinic, Mount Sinai Hospital, UCLA, University of Pennsylvania, University College London, Karolinska Institutet, King's College London, Toronto General Hospital, Mayo Clinic Proceedings, American Journal of Human Genetics, and clinical consortia such as the European Neuromuscular Centre and the Mitochondrial Medicine Society. POLG variants underlie a spectrum of mitochondrial disorders described in case series from Lancet, Nature Genetics, New England Journal of Medicine, Neurology (journal), and Annals of Neurology.

Gene and Protein Structure

The POLG gene maps to chromosome 15q24 and encodes a 140 kDa catalytic subunit composed of polymerase and exonuclease domains, with architecture elucidated by structural work from groups at European Molecular Biology Laboratory, Rudolf Virchow Center, and EMBL-EBI. Domain organization includes an N-terminal exonuclease active site homologous to bacterial Escherichia coli DNA Pol I proofreading regions and a C-terminal polymerase active site resembling family A polymerases studied in Thermus aquaticus and T7 bacteriophage. POLG exists in a holoenzyme with accessory subunits encoded by POLG2, reported in biochemical studies from Scripps Research Institute, Rockefeller University, and University of California, San Diego. Protein motifs include conserved residues identified by sequence comparisons with Saccharomyces cerevisiae Mip1 and characterized using databases maintained by UniProt, GenBank, and RefSeq.

Function and Mechanism

POLG holoenzyme catalyzes replication of circular mitochondrial genomes, coordinating with mitochondrial transcription factor A characterized at National Institute of Child Health and Human Development and helicase TWINKLE (encoded by C10orf2) studied at NIH. POLG exhibits 3'→5' exonuclease proofreading activity and 5'→3' polymerase activity; fidelity and processivity have been quantified in enzymology reports from Cold Spring Harbor Laboratory Press and Journal of Biological Chemistry. POLG activity interfaces with mitochondrial DNA repair pathways involving enzymes such as OGG1, APE1, LIG3, and proteins investigated at Institut Pasteur and Weizmann Institute of Science. Coordination with mitochondrial nucleoid proteins, including TFAM and ATAD3A, and with mitochondrial dynamics factors like OPA1 and MFN2 influences genome maintenance, as shown in studies at University of California, San Francisco and Vanderbilt University.

Clinical Significance and Associated Disorders

Mutations in POLG cause a range of mitochondrial diseases including autosomal recessive and dominant phenotypes such as progressive external ophthalmoplegia described in cohorts at Mayo Clinic, Johns Hopkins Hospital, and Royal Free Hospital, Alpers–Huttenlocher syndrome reported in case series from Children's Hospital Boston, Boston Children's Hospital, and St. Jude Children's Research Hospital, and ataxia-neuropathy syndromes documented by teams at Karolinska University Hospital and Vall d'Hebron University Hospital. POLG-related disorders present with myopathy, neuropathy, epilepsy, liver failure, and sensory deficits; natural history studies have been published in Brain (journal), Neuromuscular Disorders, and Genetics in Medicine. Allelic variants such as A467T, W748S, and Y955C have been recurrently reported in patient registries curated by ClinVar and clinical laboratories at GeneDx, Invitae, and Ambry Genetics.

Diagnosis and Genetic Testing

Diagnostic evaluation involves sequencing of POLG coding regions using next-generation platforms developed by Illumina, Thermo Fisher Scientific, and clinical pipelines at Mayo Clinic Laboratories and ARUP Laboratories, with variant interpretation guided by recommendations from the American College of Medical Genetics and Genomics and phenotype correlations cataloged in OMIM. Biochemical assays of mitochondrial function, muscle biopsy histochemistry (including ragged-red fibers noted in reports from Johns Hopkins University), and measurement of mitochondrial DNA copy number performed in centers such as UCSF Medical Center and Toronto General Hospital support diagnosis. Prenatal and preimplantation genetic testing services offered by Reproductive Medicine Associates and academic fertility centers employ targeted POLG testing for at-risk couples.

Management and Treatment

Treatment is largely supportive and multidisciplinary, with interventions provided by teams at Children's Hospital of Philadelphia, Sheffield Children's Hospital, Great Ormond Street Hospital, and regional mitochondrial clinics coordinated through networks like the North American Mitochondrial Disease Consortium. Management strategies include seizure control with medications evaluated by investigators at Johns Hopkins Epilepsy Center and Mayo Clinic Epilepsy Center, nutritional and metabolic support used in protocols from Hospital for Sick Children (Toronto), avoidance of hepatotoxic agents such as sodium valproate highlighted in alerts from FDA, and consideration of liver transplantation in select cases reported by Cleveland Clinic and Baylor College of Medicine. Experimental approaches including nucleoside bypass therapy studied at University of Cambridge and gene therapy initiatives pursued at University of Pennsylvania and industry partners like uniQure are under investigation.

Research and Model Systems

Model systems include yeast Mip1 mutants studied at University of Edinburgh, mouse Polg mutator models developed by researchers at Salk Institute and The Jackson Laboratory, and patient-derived induced pluripotent stem cells generated at Karolinska Institutet and Stanford University. Structural studies using cryo-EM and X-ray crystallography have been performed at facilities such as Diamond Light Source and Brookhaven National Laboratory. Large-scale genomics and genotype-phenotype correlations are advanced by consortia including the 100,000 Genomes Project and Exome Aggregation Consortium (ExAC). Ongoing clinical trials and translational research are registered with ClinicalTrials.gov and coordinated through networks such as the European Reference Network on Neuromuscular Diseases.

Category:Mitochondrial genetics