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- Saether, Kristine Bilgrav, et al.
(author)
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Transposable element insertions in 1000 Swedish individuals
- 2023
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:7
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Journal article (peer-reviewed)abstract
- The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at > 1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though similar to 0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (< 0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.
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- Thonberg, Håkan, 1966-
(author)
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From adrenergic signalling to gene expression : a study in brown adipocytes
- 2000
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Doctoral thesis (other academic/artistic)abstract
- Many external stimuli influence gene expression in cells by first interacting with cell surface receptors. For alteration of the expression of a gene, the signal has to be passed into the nucleus. This is facilitated by particular proteins/molecules in a signal transduction cascade. Brown adipose tissue function is mainly regulated by norepinephrine released from sympathetic nerves within the tissue. Norepinephrine controls both proliferation and differentiation of brown adipocytes, i.e. by controlling gene expression. To understand the transduction of signals from the concerted action of nor-epinephrine on various adrenergic receptors and the different signal trans-duction pathways activated, I have studied transcription factor activation and gene expression. Particular focus has been placed on the proto-oncogene c-fos and on cAMP-responsive element-mediated transcription. Stimulation of b-adrenergic receptors is mostly associated with the production of the second messenger cAMP. Elevation of cAMP activates protein kinase A, which can phosphorylate the nuclear transcription factor CREB. Stimulation of a1-adrenergic receptors is associated with activation of IP3/DAG-signalling pathways. Also, additional pathways, such as MAPK-pathways, are activated by norepinephrine stimulation in brown adipocytes, through both a1- andb-pathways.Activation of the transcription factor CREB, via phosphorylation of serine 133, was also found to be via stimulation of either a1- or b-adrenergic receptors. The kinase involved in the a1-mediated stimulation of CREB phosphorylation has not been identified, but the involvement of either a Ca2+/calmodulin-dependent kinase or a "classical" MAPK-pathway activated kinase is unlikely since there is no evidence for the existence of CaMK-proteins in brown adipocytes. Even though the MAPK-pathway is activated in our system and has been shown to mediate CREB-phosphorylation in other systems, specific inhibitors were not capable of inhibiting norepinephrine induced CREB-phosphorylation.cAMP-mediated transcription can be negatively controlled by the occurrence of repressors. ICER is one such repressor that we found to be expressed in brown adipose tissue. The expression of ICER is strictly cAMP-mediated and it may be argued that it therefore negatively regulates the CRE-mediated expression of certain genes in brown adipocytes. Since ICER is expressed in cells during proliferation, the previously proposed role of ICER as a tumour suppressor must be questioned.The expression of c-fos was found to depend on both a1- and b-adrenergic stimulation. The a1-component was sensitive to TPA-pretreatment and may thus involve protein kinase C, whereas theb-component involves the elevation of cAMP. These pathways work in synergy to induce c-fos, although the mechanism of the synergy is not understood.In conclusion, this study provides further information concerning norepinephrine signalling leading to gene transcription in brown adipocytes.
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- Thordardottir, Steinunn, et al.
(author)
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Reduced penetrance of the PSEN1 H163Y autosomal dominant Alzheimer mutation : A 22-year follow-up study
- 2018
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Journal article (peer-reviewed)abstract
- Background: The range of onset ages within some PSEN1 families is wide, and a few cases of reduced penetrance of PSEN1 mutations have been reported. However, published data on reduced penetrance have been limited to clinical histories, often collected retrospectively and lacking biomarker information. We present a case of reduced penetrance of the PSEN1 H163Y mutation in a carrier prospectively followed for 22 years. Methods: Two brothers (A and B), both carriers of the H163Y mutation, were followed between 1995 and 2017. They underwent repeated clinical evaluations, neuropsychological assessments, and cerebrospinal fluid analyses, as well as brain imaging examinations with structural magnetic resonance, [F-18] fluorodeoxyglucose positron emission tomography, and [C-11] Pittsburgh compound B positron emission tomography. Results: Brother A was followed between 44 and 64 years of age. Cognitive symptoms due to Alzheimer's disease set in at the age of 54. Gradual worsening of symptoms resulted in admittance to a nursing home owing to dependence on others for all activities of daily living. He showed a curvilinear decline in cognitive function on neuropsychological tests, and changes on magnetic resonance imaging, positron emission tomography, and biomarkers in the cerebrospinal fluid supported a clinical diagnosis of Alzheimer's disease. Brother A died at the age of 64 and fulfilled the criteria for definitive Alzheimer's disease according to neuropathological examination results. Brother B was followed between the ages of 43 and 65 and showed no cognitive deterioration on repeated neuropsychological test occasions. In addition, no biomarker evidence of Alzheimer's disease pathology was detected, either on imaging examinations or in cerebrospinal fluid. Conclusions: The average (SD) age of symptom onset for PSEN1 H163Y is 51 +/- 7 years according to previous studies. However, we present a case of a biomarker-verified reduction in penetrance in a mutation carrier who was still symptom-free at the age of 65. This suggests that other genetic, epigenetic, and/or environmental factors modify the onset age.
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- Timmons, James A, et al.
(author)
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Expression profiling following local muscle inactivity in humans provides new perspective on diabetes-related genes
- 2006
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In: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 87:1, s. 165-172
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Journal article (peer-reviewed)abstract
- Physical activity enhances muscle mitochondrial gene expression, while inactivity and mitochondrial dysfunction are both risk factors for developing diabetes. Defective activation of the transcriptional coactivator PGC-1 may contribute to the gene expression pattern observed in diabetic and insulin-resistant skeletal muscle. We proposed that greater insight into the mitochondrial component of skeletal muscle “diabetes” would be possible if the clinical transcriptome data were contrasted with local muscle inactivity-induced modulation of mitochondrial genes in otherwise healthy subjects. We studied PPARGC1A (PGC-1), PPARGC1B (PGC-1β), NRF1, and a variety of mitochondrial DNA (mtDNA) and nuclear-encoded mitochondrial genes critical for oxidative phosphorylation in soleus muscle biopsies obtained from six healthy men and women before and after 5 weeks of local muscle inactivity. Muscle inactivity resulted in a coordinated down-regulation of PGC-1 and genes involved with mitochondrial metabolism, including muscle substrate delivery genes. Decreased expression of the mtDNA helicase Twinkle was related to the decline in mitochondrial RNA polymerase (r = 0.83, p < 0.04), suggesting that mtDNA transcription and replication are coregulated in human muscle tissue. In contrast to the situation in diabetes, PGC-1β expression was not significantly altered, while NRF1 expression was actually up-regulated following muscle inactivity. We can conclude that reduced PGC-1 expression described in Type 2 diabetes may be partly explained by muscle inactivity. Further, although diabetes patients are typically inactive, our analysis indicates that local muscle inactivity may not be expected to contribute to the decreased NRF1 and PGC-1β expression noted in insulin-resistant and Type 2 diabetes patients, suggesting these changes may be more disease specific.
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