Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model.
The discovery of the c.1054C>T; p.R352W mutation in the FOXRED1 gene is a further contribution towards resolving the complex puzzle of the genetic basis of human mitochondrial disease.
Subsequent Sanger sequencing of POLG in a further 275 unrelated probands with genetically unconfirmed mitochondrial disease revealed a third unrelated proband with a similar phenotype harboring homozygous c.1879C>T; p.R627W mutations and a fourth patient, with a milder clinical disorder, harboring compound heterozygous POLG c.1879C>T; p.R627W and c.2341G>A; p.A781T mutations.
PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes.
POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders.
Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.
Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases.
We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population.
Clinical diagnosis of POLG-related disorders can be challenging because the phenotypic spectrums are heterogeneous which can mimic different types of mitochondrial disorders.