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Pathogenicity in POLG Syndromes

DNA Polymerase γ (gamma), POLG, is the sole mitochondrial replicative DNA polymerase. Its dysfunction is associated with a wide variety of disorders including AHS, MCHS, ANS, MEMSA, MIRAS, MELAS and PEO. The POLG Pathogenicity Prediction Server database currently has 709 anonymous POLG patient entries and a query interface to assess the pathogenicity of both previously reported and novel POLG mutations based on a pathogenic mutation clustering model.
Structure modeled after PDBID: 4ZTU
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Pathogenic clusters of DNA polymerase γ (POLG) catalytic subunit (POLGA)

Patient Database and Pathogenic Clusters

Pathogenic POLG mutations cluster into five distinct regions (clusters 1-5) of the three-dimensional structure of the enzyme, whereas they are distributed throughout the primary amino acid sequence. The compound heterozygous nature of the majority of POLG syndromes, combined with possible unidentified contributing genetic and/ or environmental components, results in a wide variation in their age of onset and the type and severity of symptoms, rendering difficult their diagnosis.

The POLG Pathogenicity Server combines an analysis of the structural properties of the POLG holoenzyme with existing patient data, providing a tool to support the diagnosis of possible POLG-related mitochondrial dysfunction. Our data demonstrate that the severity of a POLG syndrome correlates strongly with the age of onset of symptoms, which represents the main metric used in the analysis and interpretation of the data.

POLG primary amino acid sequence schematic with pathogenic cluster definitions (1-5)

Further information

Data and results provided on this site are subject to change as new patient data is entered into the database. The data may contain errors and should not be interpreted for any purpose without the consultation of an expert healthcare professional.

For further information, see the references page.

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