FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1239499588> ?p ?o ?g. }

• W1239499588 abstract "The central themes of this thesis are mutations of the POLG1 gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma protein, pol , their association with the wide spectrum of clinical phenotypes and tissue specificity and the biochemical characterization of particular defective mutant variants in the protein’s spacer region. PolG-holoenzyme is the sole DNA polymerase found in mitochondria. It is involved in replication and repair of the mitochondrial genome, mtDNA. Holoenzyme also includes the accessory subunit pol , which is required for the processivity of pol . Defective pol causes accumulation of secondary mutations on mtDNA, which leads to a defective oxidative phosphorylation system. The clinical consequences of such mutations are variable, affecting nervous system, skeletal muscles, liver and other post-mitotic tissues. In 2001, three PEO (Progressive External Ophthalmoplegia) -families were reported to carry either recessive or dominant mutations in the POLG1 gene. Shortly thereafter, an Italian group found novel POLG1 mutations in several Italian PEO-families. These findings prompted us to study the role of POLG1 in patients with putative mitochondrial diseases. The aims of the studies were: 1) Determination of the role of POLG1 mutations in neurological syndromes with features of mitochondrial dysfunction and an unknown molecular cause. 2) Development and set up of diagnostic tests for routine clinical purposes. 3) Biochemical characterization of the functional consequences of the identified pol variants. Clinical, molecular genetic and biochemical studies were conducted. Clinical examinations consisted of detailed neurological assessments including MRI and PET scans. Most of the genetic studies were done with PCR-based methods, including DNA sequencing, solid-phase minisequencing and denaturing highpressure liquid chromatography (dHPLC). Biochemical characterization was accomplished with the aim of baculovirus-based recombinant protein expression and subsequent purification. In vitro assays included polymerase activity, DNA binding, and processivity measurements. Studies describe new neurological phenotypes in addition to PEO caused by POLG1 mutations, including parkinsonism, premature amenorrhea, ataxia and Parkinson’s disease (PD). POLG1 mutations and polymorphisms are both common and potential genetic risk factors at least among the Finnish population. The major findings and applications reported here are: 1) POLG1 mutations cause parkinsonism and premature menopause in PEO families in either a recessive or a dominant manner. (Study I) 2) The common recessive POLG1 mutations (A467T and W748S) in the homozygous state causes severe adult or juvenile-onset spinocerebellar ataxia without muscular symptoms or histological or mtDNA abnormalities in muscles. (Study III) 3) A common recessive pathogenic change A467T can also cause a mild dominant disease in heterozygote carriers. (Study IV) 4) The A467T variant shows reduced polymerase activity due to defective template binding. (Study IV) 5) Rare polyglutamine tract length variants of POLG1 are significantly enriched in Finnish idiopathic Parkinson’s disease patients. (Study II) 6) Dominant mutations are clearly restricted to the highly conserved polymerase domain motifs, whereas recessive ones are more evenly distributed along the pol protein. (Studies I,III,IV) The present results highlight and confirm the new role of mitochondria in parkinsonism/Parkinson’s disease and describe a new mitochondrial ataxia. Based on these results, a POLG1 diagnostic routine has been set up in Helsinki University Central Hospital (HUSLAB)." @default.
• W1239499588 created "2016-06-24" @default.
• W1239499588 creator A5015249978 @default.
• W1239499588 date "2007-11-09" @default.
• W1239499588 modified "2023-09-23" @default.
• W1239499588 title "Mutations of mitochondrial DNA polymerase gamma: an important cause of neurological disorders" @default.
• W1239499588 cites W1485248300 @default.
• W1239499588 cites W1488283633 @default.
• W1239499588 cites W1490124511 @default.
• W1239499588 cites W1490199421 @default.
• W1239499588 cites W1493605791 @default.
• W1239499588 cites W1495248856 @default.
• W1239499588 cites W1503357796 @default.
• W1239499588 cites W1504584187 @default.
• W1239499588 cites W1526826406 @default.
• W1239499588 cites W1535907462 @default.
• W1239499588 cites W1536502843 @default.
• W1239499588 cites W1551996591 @default.
• W1239499588 cites W1553993431 @default.
• W1239499588 cites W1569904835 @default.
• W1239499588 cites W1595635303 @default.
• W1239499588 cites W1602460334 @default.
• W1239499588 cites W1609801461 @default.
• W1239499588 cites W1624763535 @default.
• W1239499588 cites W1656176238 @default.
• W1239499588 cites W1703028909 @default.
• W1239499588 cites W1737281046 @default.
• W1239499588 cites W1832527043 @default.
• W1239499588 cites W1940028202 @default.
• W1239499588 cites W1966206826 @default.
• W1239499588 cites W1968034613 @default.
• W1239499588 cites W1968197570 @default.
• W1239499588 cites W1968952472 @default.
• W1239499588 cites W1969717978 @default.
• W1239499588 cites W1970108838 @default.
• W1239499588 cites W1970381458 @default.
• W1239499588 cites W1971082641 @default.
• W1239499588 cites W1971681144 @default.
• W1239499588 cites W1972636956 @default.
• W1239499588 cites W1973792489 @default.
• W1239499588 cites W1974512531 @default.
• W1239499588 cites W1978422652 @default.
• W1239499588 cites W1979811481 @default.
• W1239499588 cites W1982151076 @default.
• W1239499588 cites W1982421412 @default.
• W1239499588 cites W1982911104 @default.
• W1239499588 cites W1983386499 @default.
• W1239499588 cites W1984044215 @default.
• W1239499588 cites W1985416646 @default.
• W1239499588 cites W1985921871 @default.
• W1239499588 cites W1986869352 @default.
• W1239499588 cites W1987207427 @default.
• W1239499588 cites W1988888878 @default.
• W1239499588 cites W1990265147 @default.
• W1239499588 cites W1992477424 @default.
• W1239499588 cites W1992554829 @default.
• W1239499588 cites W1993747322 @default.
• W1239499588 cites W1993770333 @default.
• W1239499588 cites W1994203444 @default.
• W1239499588 cites W1994763784 @default.
• W1239499588 cites W1995080475 @default.
• W1239499588 cites W1996052541 @default.
• W1239499588 cites W1998344938 @default.
• W1239499588 cites W1999109194 @default.
• W1239499588 cites W2000730064 @default.
• W1239499588 cites W2001256046 @default.
• W1239499588 cites W2001294987 @default.
• W1239499588 cites W2003594740 @default.
• W1239499588 cites W2003885999 @default.
• W1239499588 cites W2005928903 @default.
• W1239499588 cites W2006533372 @default.
• W1239499588 cites W2008606982 @default.
• W1239499588 cites W2010201651 @default.
• W1239499588 cites W2010236625 @default.
• W1239499588 cites W201050536 @default.
• W1239499588 cites W2010757555 @default.
• W1239499588 cites W2011000183 @default.
• W1239499588 cites W2011073385 @default.
• W1239499588 cites W2012005346 @default.
• W1239499588 cites W2013241878 @default.
• W1239499588 cites W2014254942 @default.
• W1239499588 cites W2014731403 @default.
• W1239499588 cites W2015638974 @default.
• W1239499588 cites W2015700037 @default.
• W1239499588 cites W2015762546 @default.
• W1239499588 cites W2015802342 @default.
• W1239499588 cites W2016031217 @default.
• W1239499588 cites W2016722534 @default.
• W1239499588 cites W2017347785 @default.
• W1239499588 cites W2017359142 @default.
• W1239499588 cites W2017758981 @default.
• W1239499588 cites W2018123683 @default.
• W1239499588 cites W2023941806 @default.
• W1239499588 cites W2024380916 @default.
• W1239499588 cites W2026293800 @default.
• W1239499588 cites W2026716535 @default.
• W1239499588 cites W2026779731 @default.
• W1239499588 cites W2027558057 @default.
• W1239499588 cites W2029084348 @default.
• W1239499588 cites W2029386258 @default.

• next