Association of Novel POLGMutations and Multiple Mitochondrial DNA Deletions With Variable Clinical Phenotypes in a Spanish Population

Abstract

Background: Both dominant and recessive mutations were reported in the gene encoding the mitochondrial (mt) DNA polymerase ␥ (POLG) in patients with progressive external ophthalmoplegia (PEO). Phenotypes other than PEO were recently documented in patients with mutations in the POLG gene. Objective: To screen patients with mitochondrial disease and multiple mtDNA deletions in muscle for mutations in the coding regions of the POLG, PEO1, and SLC25A4 genes. Design: To identify the underlying molecular defect in a group of patients with multiple mtDNA deletions comparing their molecular genetic findings with those of healthy controls. Patients: Twenty-four patients (16 men and 8 women) diagnosed with mitochondrial disease and having multiple mtDNA deletions in muscle by Southern blot analysis. Thirteen patients had PEO; 2 had PEO alone, 4 had PEO and myopathy, and 5 had PEO and multisystem involvement. Four patients had multisystem disease without PEO. The remaining 9 patients had isolated myopathy. DNA from 100 healthy individuals was also studied. Results: No mutation was identified in the PEO1 or SLC25A4 genes. Nine POLG mutations were observed in 6 of 24 patients. Four novel mutations were detected and mapped in the linker region (M603L) and in the pol domain of the enzyme (R853W; D1184N; R1146C). Five patients with PEO had mutations: 2 were compound heterozygotes, 1 was homozygous, and another showed a mutation in a single allele. The remaining patient also showed a sole mutation and had an unusual phenotype lacking ocular involvement. Conclusions: POLG molecular defects were found in 25% of our patients with multiple mtDNA deletions and mitochondrial disease. The uncommon phenotype found in 1 of these patients stresses the clinical variability of patients harboring POLG mutations. Molecular studies in the POLG gene should be addressed in patients with mitochondrial disease, particularly in those with PEO, and multiple mtDNA deletions.

Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ

“…Residues on the inside of the incoming nucleotide play important roles in replication fidelity. The substitution A1105T promotes slipped mispairing, leading to increased insertion/deletion mutations, and R853W/Q substitutions result in increased mtDNA mutations (27,28). The positively charged residues on the O-helix fingers domain are exclusively involved in triphosphate binding.…”

Disease Mutations in the Human Mitochondrial DNA Polymerase Thumb Subdomain Impart Severe Defects in Mitochondrial DNA Replication

“…The R853W mutation is associated with autosomal recessive PEO when found in trans with P587L (33), and compound heterozygotes pairing R853W in trans with G737R can cause parkinsonism in the absence of PEO (34). The R853Q mutation in trans with T251I-P587L is associated with myocerebrohepatopathy in a patient that presented at 2-3 months of age.…”

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

“…For instance, extracting muscle to assay electron transport chain complex activity is useful in identifying mitochondrial cytopathy, but not necessarily POLG-related diseases (Gonzalez-Vioque et al 2006;de Vries et al 2007;. In addition, the use of mitochondrial DNA (mtDNA) depletion assays can be misleading for two reasons: normal mtDNAvalues would not exclude POLG disease, especially early in the course of the disease, and (Hirano et al 1994).…”