Disease relevance of POLG

• Mutation of the nuclear gene for the catalytic subunit of pol gamma (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA [1].
• ANT1, Twinkle, POLG, and TP: new genes open our eyes to ophthalmoplegia [2].
• OBJECTIVE: To identify POLG mutations in patients with sensory ataxia and CNS features [3].
• Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations [3].
• POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness [4].
• Even in the absence of classic features of mitochondrial disease, POLG1 should be considered in patients having axonal CMT that may be associated with tremor or ataxia [5].

Psychiatry related information on POLG

• Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation [6].

High impact information on POLG

• Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions [7].
• POLG is the only DNA polymerase responsible for mtDNA replication [7].
• Analysis of POLG genotypes in different populations identified an association between absence of the common, ten-repeat allele and male infertility typified by a range of sperm quality defects but excluding azoospermia [8].
• These findings suggest that Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga and provide genetic evidence of the necessity for mitochondrial Hsp40 in preventing DCM [9].
• Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G [10].

Chemical compound and disease context of POLG

• RECENT FINDINGS: Most recently described mitochondrial myopathies are due to defects in nuclear DNA, including coenzyme Q10 deficiency, and mutations in genes that control mitochondrial DNA (mtDNA) abundance and structure such as POLG and TK2 [11].
• The aim of this study was to evaluate the exercise capacity and lactate kinetics related to exercise in subjects with two genetically characterized mitochondrial disorders (multiple mitochondrial DNA deletions with PEO, MELAS) compared with lactate kinetics in subjects with metabolic myopathy (McArdle's disease) and in the healthy controls [12].

Biological context of POLG

• We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families [7].
• Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population [13].
• Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia [14].
• Autosomal dominant progressive external ophthalmoplegia (adPEO) is caused by mutations in at least three different genes: ANT1 (chromosome 4q34-35), TWINKLE, and POLG [15].
• A prevalent POLG CAG microsatellite length allele in humans and African great apes [16].

Anatomical context of POLG

• By expressing POLG fusion proteins in cultured human cells, we show that the enzyme is targeted to mitochondria, where the Myc epitope-tagged POLG is catalytically active as a DNA polymerase [17].
• In all subjects, the POLG polymorphism was assessed in relation to their semen quality, and--in the fertile controls--with biological fecundity measured as waiting time-to-pregnancy (TTP) for the couples [18].
• Comparison between the CAG repeat length distribution of control and Parkinson's disease samples revealed no evidence of either germ line or somatic POLG CAG repeat instability in Parkinson's disease patients [19].
• Thus, the differential distribution of fibers with extremely high concentrations of mutant mtDNAs characterizes, and probably distinguishes, the skeletal muscle of PEO and MELAS patients harboring the same nt-3243 mutation [20].
• The neuromuscular signs were PEO, dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss [21].

Associations of POLG with chemical compounds

• The human nuclear gene for the catalytic subunit of mitochondrial DNA polymerase gamma ( POLG) contains within its coding region a CAG microsatellite encoding a polyglutamine repeat [16].
• The self-assembly of triblock copolymers of poly(ethylene oxide-b-methyl methacrylate-b-styrene) (PEO-b-PMMA-b-PS), where PS is the major component and PMMA and PEO are minor components, provides a robust route to highly ordered, nanoporous arrays with cylindrical pores of 10-15 nm that show promise in block copolymer lithography [22].
• Temperature-induced reversible morphological changes of polystyrene-block-poly(ethylene oxide) micelles with degrees of polymerization of 962 for the PS and 227 for the PEO blocks (PS962-b-PEO227) in N,N-dimethylformamide (DMF)/water, in which water is a selective solvent for the PEO block, were observed [23].
• The distribution, dynamics, and local environments of the TFA-modified titania, PEO, and PPO components of the hybrid were investigated [24].
• The viscosity-adjustable property of F127 block copolymer PEO99PPO69PEO99, PEO and PPO being poly(ethylene oxide) and poly(propylene oxide), respectively, was found to be useful for the development of automated capillary electrophoresis (CE) [25].

Other interactions of POLG

• Mutations in POLG can also cause autosomal recessive PEO, which is often associated with multisystemic disorders [26].
• Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay [27].
• In addition, one 'homozygous mutant' was identified in 91 fertile men (1.1%) CONCLUSION: Under our conditions, our study does not confirm any relationship between the polymorphic CAG repeat in the POLG gene and male infertility [28].
• Analysis of POLG in other primates indicates that the repeat has expanded from a shorter, glutamine-rich sequence, present in the common ancestor of Old and New World monkeys [16].
• We suggest that abnormal expression of factors such as TFAM and POLG in NT embryos will prematurely drive mtDNA replication, hence impacting on early development [29].

Analytical, diagnostic and therapeutic context of POLG

• In the patients lacking the common POLG allele, the outcome of the assisted reproductive techniques (ART) for the couples was evaluated [18].
• Sequence analysis of the POLG CAG microsatellite region of more than 1000 human chromosomes reveals that virtually all allelic variation at the locus is accounted for by length variation of the CAG repeat [16].
• Fluorescence in situ hybridization (FISH) of human and mouse bacterial artificial chromosomes (BACs), hybridized by radioactively labeled POLG cDNAs, mapped to human chromosome band 15q24-->q26, as well as to mouse chromosome band 7E [30].
• Southern blotting and real time PCR were used to detect deletions of mtDNA and mutations in the POLG gene were identified using a combination of DHPLC and direct DNA sequencing [31].
• Study of copper sulfide crystallization in PEO-SDS solutions [32].

References