Molecular and clinical genetics of mitochondrial diseases due to POLG mutations

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Human Mutation (Impact Factor: 5.05). 09/2008; 29(9):E150-72. DOI: 10.1002/humu.20824
Source: PubMed

ABSTRACT Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.

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    ABSTRACT: Background and aims: Patients with mutations in the POLG1 gene encoding the mitochondrial DNA polymerase gamma have an increased risk of valproate-induced liver failure. POLG1 mutations are common among populations and these patients often suffer from intractable seizures. The role of liver transplantation in the treatment of patients with mitochondrial diseases has been controversial. We studied valproate-induced liver failure associated with POLG1 mutations and the prognosis of these patients after liver transplantation.Methods: POLG1 was analyzed in blood DNA, mitochondrial DNA (mtDNA) was quantified in liver samples and clinical data was collected.Results: Five patients with valproate-induced liver failure associated with POLG1 mutations were retrospectively identified. Three patients were previously suspected to have Wilson’s disease. Four patients with homozygous p.W748S and p.E1143G mutations had mtDNA depletion in the liver. One of these patients had died prior to anticipated transplantation, the other three patients with liver transplantation have survived from 4 to 19 years. Two patients present with occasional epileptic seizures and one patient has been seizure free for 11 years. One patient with a heterozygous p.Q1236H mutation, but without mtDNA depletion in the liver, died suddenly two years after the liver transplantation.Conclusions: The POLG1 mutation status and the age at presentation of valproate-induced liver failure can affect the prognosis after liver transplantation. A heterozygous POLG1 p.Q1236H mutation was related to valproate-induced liver failure without mtDNA depletion, whereas patients homozygous for POLG1 p.W748S and p.E1143G mutations had mtDNA depletion. Analysis of the POLG1 gene should be performed for all patients with suspected mitochondrial disease before introducing valproate therapy and treatment with valproic acid should be avoided in these patients. Liver Transpl , 2014. © 2014 AASLD.
    Liver Transplantation 11/2014; 20(11). DOI:10.1002/lt.23965 · 3.79 Impact Factor
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    ABSTRACT: Mitochondrial DNA maintenance disorders are an important cause of hereditary ataxia syndrome, and the majority are associated with mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (DNA polymerase gamma), POLG. Mutations resulting in the amino acid substitutions A467T and W748S are the most common genetic causes of inherited cerebellar ataxia in Europe. We report here a POLG mutational screening in a family with a mitochondrial ataxia phenotype. To evaluate the likely pathogenicity of each of the identified changes, a 3D structural analysis of the PolG protein was carried out, using the Alpers mutation clustering tool reported previously. Three novel nucleotide changes and the p.Q1236H polymorphism have been identified in the affected members of the pedigree. Computational analysis suggests that the p.K601E mutation is likely the major contributing factor to the pathogenic phenotype. Computational analysis of the PolG protein suggests that the p.K601E mutation is likely the most significant contributing factor to a pathogenic phenotype. However, the co-occurrence of multiple POLG alleles may be necessary in the development an adult-onset mitochondrial ataxia phenotype.
    BMC Research Notes 12/2014; 7(1):883. DOI:10.1186/1756-0500-7-883
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    ABSTRACT: Several pathological mutations have been identified in human POLG gene, encoding for the catalytic subunit of Pol γ, the solely mitochondrial replicase in animals and fungi. However, little is known regarding non-pathological polymorphisms found in this gene. Here we studied, in the yeast model Saccharomyces cerevisiae, eight human polymorphisms. We found that most of them are not neutral but enhanced both mtDNA extended mutability and the accumulation of mtDNA point mutations, either alone or in combination with a pathological mutation. In addition, we found that the presence of some SNPs increased the stavudine and/or zalcitabine-induced mtDNA mutability and instability.
    Mitochondrion 11/2014; 20. DOI:10.1016/j.mito.2014.11.003 · 3.52 Impact Factor

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