| 1. |
- Erdinc, Direnis, et al.
(author)
-
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
-
In: Embo Molecular Medicine. - 1757-4676. ; 15:5
-
Journal article (peer-reviewed)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
|
|
| 2. |
- Chaffin, Brian C., et al.
(author)
-
Biological invasions, ecological resilience and adaptive governance
- 2016
-
In: Journal of Environmental Management. - : Elsevier BV. - 0301-4797 .- 1095-8630. ; 183, s. 399-407
-
Journal article (peer-reviewed)abstract
- In a world of increasing interconnections in global trade as well as rapid change in climate and land cover, the accelerating introduction and spread of invasive species is a critical concern due to associated negative social and ecological impacts, both real and perceived. Much of the societal response to invasive species to date has been associated with negative economic consequences of invasions. This response has shaped a war-like approach to addressing invasions, one with an agenda of eradications and intense ecological restoration efforts towards prior or more desirable ecological regimes. This trajectory often ignores the concept of ecological resilience and associated approaches of resilience-based governance. We argue that the relationship between ecological resilience and invasive species has been understudied to the detriment of attempts to govern invasions, and that most management actions fail, primarily because they do not incorporate adaptive, learning-based approaches. Invasive species can decrease resilience by reducing the biodiversity that underpins ecological functions and processes, making ecosystems more prone to regime shifts. However, invasions do not always result in a shift to an alternative regime; invasions can also increase resilience by introducing novelty, replacing lost ecological functions or adding redundancy that strengthens already existing structures and processes in an ecosystem. This paper examines the potential impacts of species invasions on the resilience of ecosystems and suggests that resilience-based approaches can inform policy by linking the governance of biological invasions to the negotiation of tradeoffs between ecosystem services.
|
|
| 3. |
- Peter, Bradley, et al.
(author)
-
Defective mitochondrial protease LonP1 can cause classical mitochondrial disease
- 2018
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1743-1753
-
Journal article (peer-reviewed)abstract
- LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues.
|
|
