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.

Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations

“…Normal oxidative phosphorylation system (OXPHOS) studies were found in six patients by Nguyen and colleagues [22]. Various combinations of enzyme deficiencies in adults, as seen in our patients, have recently been observed by González-Vioque and colleagues as well [8]. In addition, we observed severely decreased ATP production and oxidation rates in all of our patients.…”

“…We observed a high frequency of POLG1 mutations as well in children. Several reports have recently described patients, especially adults, with a mutation in the polymerase gamma gene [4,6,8,12,13,19,22,25,30]. The clinical picture in our patients was a progressive multi-system disorder.…”

Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations

“…Normal oxidative phosphorylation system (OXPHOS) studies were found in six patients by Nguyen and colleagues [22]. Various combinations of enzyme deficiencies in adults, as seen in our patients, have recently been observed by González-Vioque and colleagues as well [8]. In addition, we observed severely decreased ATP production and oxidation rates in all of our patients.…”

“…We observed a high frequency of POLG1 mutations as well in children. Several reports have recently described patients, especially adults, with a mutation in the polymerase gamma gene [4,6,8,12,13,19,22,25,30]. The clinical picture in our patients was a progressive multi-system disorder.…”

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

“…Pathogenicity of the p.R597W substitution is predicted from pedigree analysis which showed family members to be unaffected heterozygous carriers. Moreover, the mutation occurs close to the previously reported pathogenic changes (p.P587L and p.M603L) within the linker region 25 26…”

Dystonia in a Patient with Autosomal‐Dominant Progressive External Ophthalmoplegia Type 1 Caused by Mutation in the POLG Gene

“…A heterozygous variant c.3436C>T in exon 21 of the POLG gene, which results in a missense p.Arg1146Cys change, was detected. This mutation is consistent with a genetic diagnosis of adPEO1 . The same variant was also detected in a heterozygous state in the patient's mother.…”

Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations

“…Normal oxidative phosphorylation system (OXPHOS) studies were found in six patients by Nguyen and colleagues [22]. Various combinations of enzyme deficiencies in adults, as seen in our patients, have recently been observed by González-Vioque and colleagues as well [8]. In addition, we observed severely decreased ATP production and oxidation rates in all of our patients.…”

“…We observed a high frequency of POLG1 mutations as well in children. Several reports have recently described patients, especially adults, with a mutation in the polymerase gamma gene [4,6,8,12,13,19,22,25,30]. The clinical picture in our patients was a progressive multi-system disorder.…”

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

“…Pathogenicity of the p.R597W substitution is predicted from pedigree analysis which showed family members to be unaffected heterozygous carriers. Moreover, the mutation occurs close to the previously reported pathogenic changes (p.P587L and p.M603L) within the linker region 25 26…”

Dystonia in a Patient with Autosomal‐Dominant Progressive External Ophthalmoplegia Type 1 Caused by Mutation in the POLG Gene

“…A heterozygous variant c.3436C>T in exon 21 of the POLG gene, which results in a missense p.Arg1146Cys change, was detected. This mutation is consistent with a genetic diagnosis of adPEO1 . The same variant was also detected in a heterozygous state in the patient's mother.…”

Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations

“…Normal oxidative phosphorylation system (OXPHOS) studies were found in six patients by Nguyen and colleagues [22]. Various combinations of enzyme deficiencies in adults, as seen in our patients, have recently been observed by González-Vioque and colleagues as well [8]. In addition, we observed severely decreased ATP production and oxidation rates in all of our patients.…”

“…We observed a high frequency of POLG1 mutations as well in children. Several reports have recently described patients, especially adults, with a mutation in the polymerase gamma gene [4,6,8,12,13,19,22,25,30]. The clinical picture in our patients was a progressive multi-system disorder.…”

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

“…Pathogenicity of the p.R597W substitution is predicted from pedigree analysis which showed family members to be unaffected heterozygous carriers. Moreover, the mutation occurs close to the previously reported pathogenic changes (p.P587L and p.M603L) within the linker region 25 26…”

Dystonia in a Patient with Autosomal‐Dominant Progressive External Ophthalmoplegia Type 1 Caused by Mutation in the POLG Gene

“…A heterozygous variant c.3436C>T in exon 21 of the POLG gene, which results in a missense p.Arg1146Cys change, was detected. This mutation is consistent with a genetic diagnosis of adPEO1 . The same variant was also detected in a heterozygous state in the patient's mother.…”