Mutations In Polymerase Gamma Gene Research Articles

POLG Mutations Are Probably Rare in the Han Chinese Population

Objective Mutations in polymerase gamma gene (POLG) are believed to be an important cause of early and juvenile onset of non-syndromic intractable epilepsy. The aim of this study is to investigate the incidence/prevalence of POLG pathogenic variants in epilespy patients of Han population through sequencing it.Methods Han Chinese patients with seizures prior valproic acid (VPA) exposure at Shanghai Children's Hospital were collected from 2015 to 2019. The clinical diagnosis was based on the 2014 Consensus Statement of Epilepsy by the International League against Epilepsy (ILAE). Blood sampling were performed before VPA treatment. The POLG gene DNA was sequenced by either the first or the next generation sequencing (NGS). The POLG variant burden was illustrated. Liver functions were tested to describe whether they experienced VPA toxicity.Results Totally 216 Han Chinese patients were included, aged from 1 month to 15 years old, 102 were male and 114 were female. The onset age was 1 month old to 13 years old, and the epilepsy course ranged from 2 weeks to about 3 years. VPA treatment was delivered for the generalized or intractable partial seizures at standard dosage. No patient experienced hepatic toxicity following VPA exposure. DNA sequencing data showed no patient had either a homozygous mutation or compound heterozygous mutation of POLG. Single heterozygous mutations of c.1150G>T and p.D384Y were found in 2 patients, and single heterozygous mutation of c.156_158dupGCA was found in 1 patient. None of these variants showed clinical significance.Conclusions Functional modifying POLG homozygous mutations and compound heterozygous mutations were not detected and VPA toxicity was not seen in the current study. POLG mutation frequency might be rare in Han Chinese, and standard VPA therapeutic dosage might be safe for Han Chinese patients.

Mitochondrial DNA Polymerase γ Mutations and Their Implications in mtDNA Alterations in Colorectal Cancer.

Mitochondrial DNA was found to be highly mutated in colorectal cancer cells. One of the key molecules involved in the maintenance of the mitochondrial genome is the nuclear-encoded polymerase gamma. The aim of our study was to determine if there is a link between polymorphisms within the polymerase gamma gene (POLG) and somatic mutations within the mitochondrial genome in cancer cells. We investigated POLG sequence variability in 50 colorectal cancer patients whose complete mitochondrial genome sequences were determined. Relative mtDNA copy number was also determined. We identified 251 sequence variants in the POLG gene. Most of them were germline-specific (∼92%). Twenty-one somatic changes in POLG were found in 10 colorectal cancer patients. We have found no association between the occurrence of mtDNA somatic mutations and the somatically occurring variants in POLG. MtDNA content was reduced in patients carrying somatic variants in POLG or germline nucleotide variants located in the region encoding the POLG polymerase domain, but the difference did not reach statistical significance. Our findings suggest that somatic mtDNA mutations occurring in colorectal cancer are not a consequence of somatic mutations in POLG. Nevertheless, POLG nucleotide variants may lead to a decrease in mtDNA content, and consequently result in mitochondrial dysfunction.

The POLG Polyglutamine Tract Variants in Iranian Patients with Multiple Sclerosis.

Multiple Sclerosis (MS) is a common disease of the central nervous system. The interaction between inflammatory and neurodegenerative processes typically results in irregular neurological disturbances followed by progressive disability. Mitochondrial dysfunction has been implicated in neurodegenerative disorders. The DNA polymerase-gamma (POLG) gene, which encodes the catalytic subunit of enzyme responsible for directing mtDNA replication, contains a poly glutamine tract (poly-Q) in the N-terminal, encoded by a CAG sequence in exon 2. We analyzed the POLG trinucleotide repeats in 40 Iranian patients with MS (27 females and 13 males with an age range of 18-55); and 47 healthy age, gender, and ethnic matched controls were chosen by PCR-SSCP analysis. Our results indicated that the most common allele in patients had 10 consecutive CAG repeats (10Q). Other alleles of 11and 12 trinucleotide repeats were detected. We did not find any difference between the CAG repeat length distribution in controls and MS patients. No correlation was observed in the POLG gene CAG repeat with pathogenesis of MS, but it looks that other point mutations in POLG gene may have an important role in the disease's pathogenesis and produced more significant results.

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene

SummaryBackgroundPOLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion.Material/MethodsA cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations.ResultsThe p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion).ConclusionsOur results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.

Compound Heterozygous Polymerase Gamma Gene Mutation in a Patient With Alpers Disease

Alpers disease is a mitochondrial depletion syndrome characterized by psychomotor retardation, intractable epilepsy, and liver failure. Polymerase gamma (POLG) gene mutations are a known cause of the disease. We describe a case in which a 14-month-old female presented with epilepsia partialis continua evolving into generalized status epilepticus. Treatment with multiple antiepileptic medications and the ketogenic diet eliminated her seizures, but she remained severely encephalopathic. Magnetic resonance imaging showed diffuse atrophy of gray-matter structures. She ultimately developed liver failure and died. Mitochondrial analysis revealed compound heterozygosity for 3 POLG gene mutations, 2 of which were previously unreported.

POLG mutations and Alpers syndrome

Alpers-Huttenlocher syndrome (AHS) an autosomal recessive hepatocerebral syndrome of early onset, has been associated with mitochondrial DNA (mtDNA) depletion and mutations in polymerase gamma gene (POLG). We have identified POLG mutations in four patients with hepatocerebral syndrome and mtDNA depletion in liver, who fulfilled criteria for AHS. All were compound heterozygous for the G848S and W748S mutations, previously reported in patients with progressive external ophtalmoplegia or ataxia. We conclude that AHS should be included in the clinical spectrum of mtDNA depletion and is often associated with POLG mutations, which can cause either multiple mtDNA deletions or mtDNA depletion.

Comparative mapping of the POLG gene to cattle chromosome 21q17→q22 by FISH and confirmation by RH mapping

The DNA directed polymerase gamma gene (POLG), known to be located on human chromosome (HSA) 15q25 (Walker et al., 1997), encodes the only DNA polymerase responsible for mitochondrial DNA (mtDNA) replication. Mutations in human POLG have been identified in affected families with progressive external ophthalmoplegia (PEO) characterized by accumulation of large-scale mitochondrial DNA deletions (OMIM #157640; Van Goethem et al., 2001). This gene was identified as candidate gene for congenital bilateral convergent strabismus with exophthalmus (BCSE) in cattle (OMIA 000353; Distl, 1993; Distl and Gerst, 2000). This monogenic autosomal dominant inherited phenotype in cattle shows similarities to the heterogeneous dominant and recessive forms of PEO in man, e.g. eye muscle biopsies of affected humans and cattle demonstrated the presence of ragged red fibers and many mtDNA deletions (Li et al., 1999). Application of a comparative approach, using a human cDNA to screen a bovine BAC library revealed a POLG-containing bovine BAC clone. To facilitate future linkage studies we report the physical mapping of the bovine POLG gene to cattle chromosome (BTA) 21q17→q22 by FISH and RH mapping.