| 1. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 2. |
- Hibar, D. P., et al.
(författare)
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Cortical abnormalities in bipolar disorder: An MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group
- 2018
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 23:4, s. 932-942
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Tidskriftsartikel (refereegranskat)abstract
- Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d='0.293; P=1.71 × 10 '21), left fusiform gyrus (d='0.288; P=8.25 × 10 '21) and left rostral middle frontal cortex (d='0.276; P=2.99 × 10 '19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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| 3. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 4. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 5. |
- Hibar, D. P., et al.
(författare)
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Subcortical volumetric abnormalities in bipolar disorder
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:12, s. 1710-1716
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Tidskriftsartikel (refereegranskat)abstract
- Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10 -7) and thalamus (d=-0.148; P=4.27 × 10 -3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10 -5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons. © 2016 Macmillan Publishers Limited, part of Springer Nature.
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| 6. |
- Govaere, O., et al.
(författare)
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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors
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| 7. |
- Amare, Azmeraw T, et al.
(författare)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
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| 8. |
- Kurzawa-Akanbi, M., et al.
(författare)
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Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders
- 2021
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 142, s. 961-984
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)-collectively Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and alpha-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a "pathological package" capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein-ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.
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| 9. |
- Augustin, S., et al.
(författare)
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Signatures of autoionization in the angular electron distribution in two-photon double ionization of Ar
- 2018
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Ingår i: Physical Review A. - 2469-9926. ; 98:3
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Tidskriftsartikel (refereegranskat)abstract
- A kinematically complete experiment on two-photon double ionization of Ar by free-electron laser radiation with a photon energy of 27.93 eV was performed. The electron energy spectra show that double ionization is dominated by the sequential process. Comparison of the electron angular distributions to our data for single ionization and to theory confirms that even in the sequential process the electrons from both ionization steps are correlated with each other through polarization of the intermediate Ar+ state. Furthermore, a very important role of autoionization in both ionization steps is found.
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| 10. |
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| 11. |
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| 12. |
- Gandin, V, et al.
(författare)
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mTORC1 and CK2 coordinate ternary and eIF4F complex assembly
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 11127-
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Tidskriftsartikel (refereegranskat)abstract
- Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.
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| 13. |
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| 14. |
- Rozema, J, et al.
(författare)
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The role of UV-B radiation in aquatic and terrestrial ecosystems—an experimental and functional analysis of the evolution of UV-absorbing compounds
- 2002
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Ingår i: Journal of Photochemistry and Photobiology, B: Biology. - 1011-1344. ; 66:1, s. 2-12
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Tidskriftsartikel (refereegranskat)abstract
- We analysed and compared the functioning of UV-B screening pigments in plants from marine, fresh water and terrestrial ecosystems, along the evolutionary line of cyanobacteria, unicellular algae, primitive multicellular algae, charophycean algae, lichens, mosses and higher plants, including amphibious macrophytes. Lichens were also included in the study. We were interested in the following key aspects: (a) does the water column function effectively as an ‘external UV-B filter’?; (b) do aquatic plants need less ‘internal UV-B screening’ than terrestrial plants?; (c) what role does UV screening play in protecting the various plant groups from UV-B damage, such as the formation of thymine dimers?; and (d) since early land ‘plants’ (such as the predecessors of present-day cyanobacteria, lichens and mosses) experienced higher UV-B fluxes than higher plants, which evolved later, are primitive aquatic and land organisms (cyanobacteria, algae, lichens, mosses) better adapted to present-day levels of UV-B than higher plants? Furthermore, polychromatic action spectra for the induction of UV screening pigments of aquatic organisms have been determined. This is relevant for translating ‘physical’ radiation measurements of solar UV-B into ‘biological’ and ‘ecological’ effects. From the action spectra, radiation amplification factors (RAFs) have been calculated. These action spectra allow us to determine any mitigating or antagonistic effects in the ecosystems and therefore qualify the damage prediction for the ecosystems under study. We summarize and discuss the main results based on three years of research of four European research groups. The central theme of the work was the investigation of the effectiveness of the various screening compounds from the different species studied in order to gain some perspective of the evolutionary adaptations from lower to higher plant forms. The induction of mycosporine-like amino acids (MAAs) was studied in the marine dinoflagellate Gyrodinium dorsum, the green algal species Prasiola stipitata and in the cyanobacterium Anabaena sp. While visible (400–700 nm) and long wavelength UV-A (315–400 nm) showed only a slight effect, MAAs were effectively induced by UV-B (280–315 nm). The growth of the lower land organisms studied, i.e. the lichens Cladina portentosa, Cladina foliacaea and Cladonia arbuscula, and the club moss Lycopodiumannotinum, was not significantly reduced when grown under elevated UV-B radiation (simulating 15% ozone depletion). The growth in length of the moss Tortula ruralis was reduced under elevated UV-B. Of the aquatic plants investigated the charophytes Chara aspera showed decreased longitudinal growth under elevated UV-B. In the ‘aquatic higher plants’ studied, Ceratophyllum demersum, Batrachium trichophyllum and Potamogeton alpinus, there was no such depressed growth with enhanced UV-B. In Chara aspera, neither MAAs nor flavonoids could be detected. Of the terrestrial higher plants studied, Fagopyrum esculentum, Deschampsia antarctica, Vicia faba, Calamagrostis epigejos and Carex arenaria, the growth of the first species was depressed with enhanced UV-B, in the second species length growth was decreased, but the shoot number was increased, and in the latter two species of a dune grassland there was no reduced growth with enhanced UV-B. In the dune grassland species studied outdoors, at least five different flavonoids appeared in shoot tissue. Some of the flavonoids in the monocot species, which were identified and quantified with HPLC, included orientin, luteolin, tricin and apigenin. A greenhouse study with Vicia faba showed that two flavonoids (aglycones) respond particularly to enhanced UV-B. Of these, quercetin is UV-B inducible and mainly located in epidermal cells, while kaempferol occurs constitutively. In addition to its UV-screening function, quercetin may also act as an antioxidant. Polychromatic action spectra were determined for induction of the UV-absorbing pigments in three photosynthetic organisms, representing very different taxonomic groups and different habitats. In ultraviolet photobiology, action spectra mainly serve two purposes: (1) identification of the molecular species involved in light absorption; and (2) calculation of radiation amplification factors for assessing the effect of ozone depletion. Radiation amplification factors (RAFs) were calculated from the action spectra. In a somewhat simplified way, RAF can be defined as the percent increase of radiation damage for a 1% depletion of the ozone layer. Central European summer conditions were used in the calculations, but it has been shown that RAF values are not critically dependent on latitude or season. If only the ultraviolet spectral region is considered, the RAF values obtained are 0.7 for the green alga Prasiola stipitata, 0.4 for the dinoflagellate Gyrodinium dorsum, and 1.0 for the cyanobacterium Anabaena sp. In the case of P. stipitata, however, the effect of visible light (PAR, photosynthetically active radiation, 400–700 nm) is sufficient to lower the RAF to about 0.4, while the PAR effect for G. dorsum is negligible. RAFs for some damage processes, such as for DNA damage (RAF=2.1 if protective effects or photorepair are not considered [1]), are higher than those above. Our interpretation of this is that if the ozone layer is depleted, increased damaging radiation could overrule increased synthesis of protective pigments. In addition to investigating the functional effectiveness of the different screening compounds, direct UV effects on a number of key processes were also studied in order to gain further insight into the ability of the organisms to withstand enhanced UV-B radiation. To this end, the temperature-dependent repair of cyclobutane dimers (CPD) and (6–4) photoproducts induced by enhanced UV-B was studied in Nicotiana tabacum, and the UV-B induction of CPD was studied in the lichen Cladonia arbuscula [2]. Also, photosynthesis and motility were monitored and the response related to the potential function of the screening compounds of the specific organism.
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| 15. |
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| 16. |
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| 17. |
- Gaberscik, A, et al.
(författare)
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The influence of enhanced UV-B radiation on the spring geophyte Pulmonaria officinalis
- 2001
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Ingår i: Plant Ecology. - 1573-5052. ; 154:1-2, s. 49-56
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonaria officinalis is an understorey spring geophyte, which starts its vegetative period before full foliation of the tree storey. During its early growth phase it is exposed to full solar radiation, therefore the enhanced UV-B radiation could present a threat to this species. An outdoor experiment in which potted plants were exposed to below ambient, ambient, and above ambient (corresponding to 17% ozone reduction) UV-B radiation, was conducted in order to evaluate the radiation effects. The amount of photosynthetic pigments and photochemical efficiency of PSII were not affected, but the amount of UV-B absorbing compounds was lower in plants grown under reduced UV-B. This change was measurable after only fourteen days in reproductive shoots, while in the vegetative shoots, it was not detectable until after three months. The leaves of P. officinalis are variegated and the light green spots became less transparent to PAR under enhanced UV-B. The results reveal that under simulated 17% ozone depletion the harmful effects of UV-B on the measured parameters were negligible. This is the final, accepted and revised manuscript of this article. Use alternative location to go to the published article. Requires subscription. The original publication is available at www.springerlink.com.
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| 18. |
- Gassner, Christoph, et al.
(författare)
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Two Prevalent ∼100-kb GYPB Deletions Causative of the GPB-Deficient Blood Group MNS Phenotype S-s-U-in Black Africans
- 2020
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Ingår i: Transfusion Medicine and Hemotherapy. - : S. Karger AG. - 1660-3796 .- 1660-3818. ; 47:4, s. 326-336
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Tidskriftsartikel (refereegranskat)abstract
- The U antigen (MNS5) is one of 49 antigens belonging to the MNS blood group system (ISBT002) carried on glycophorins A (GPA) and B (GPB). U is present on the red blood cells in almost all Europeans and Asians but absent in approximately 1.0% of Black Africans. U negativity coincides with negativity for S (MNS3) and s (MNS4) on GPB, thus be called S-s-U-, and is thought to arise from homozygous deletion of GYPB. Little is known about the molecular background of these deletions. Bioinformatic analysis of the 1000 Genomes Project data revealed several candidate regions with apparent deletions in GYPB. Highly specific Gap-PCRs, only resulting in positive amplification from DNAs with deletions present, allowed for the exact genetic localization of 3 different breakpoints; 110.24- A nd 103.26-kb deletions were proven to be the most frequent in Black Americans and Africans. Among 157 CEPH DNAs, deletions in 6 out of 8 African ethnicities were present. Allele frequencies of the deletions within African ethnicities varied greatly and reached a cumulative 23.3% among the Mbuti Pygmy people from the Congo. Similar observations were made for U+var alleles, known to cause strongly reduced GPB expression. The 110- A nd 103-kb deletional GYPB haplotypes were found to represent the most prevalent hereditary factors causative of the MNS blood group phenotype S-s-U-. Respective GYPB deletions are now accessible by molecular detection of homo- A nd hemizygous transmission.
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| 19. |
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| 20. |
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| 21. |
- Petric, B, et al.
(författare)
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Investigation of Paraoxonase-1 Genotype and Enzyme-Kinetic Parameters in the Context of Cognitive Impairment in Parkinson's Disease
- 2023
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Ingår i: Antioxidants (Basel, Switzerland). - : MDPI AG. - 2076-3921. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive impairment is a common non-motor symptom of Parkinson’s disease (PD), which often progresses to PD dementia. PD patients with and without dementia may differ in certain biochemical parameters, which could thus be used as biomarkers for PD dementia. The enzyme paraoxonase 1 (PON1) has previously been investigated as a potential biomarker in the context of other types of dementia. In a cohort of PD patients, we compared a group of 89 patients with cognitive impairment with a group of 118 patients with normal cognition. We determined the kinetic parameters Km and Vmax for PON1 for the reaction with dihydrocoumarin and the genotype of four single nucleotide polymorphisms in PON1. We found that no genotype or kinetic parameter correlated significantly with cognitive impairment in PD patients. However, we observed associations between PON1 rs662 and PON1 Km (p < 10−10), between PON1 rs662 and PON1 Vmax (p = 9.33 × 10−7), and between PON1 rs705379 and PON1 Vmax (p = 2.21 × 10−10). The present study is novel in three main aspects. (1) It is the first study to investigate associations between the PON1 genotype and enzyme kinetics in a large number of subjects. (2) It is the first study to report kinetic parameters of PON1 in a large number of subjects and to use time-concentration progress curves instead of initial velocities to determine Km and Vmax in a clinical context. (3) It is also the first study to calculate enzyme-kinetic parameters in a clinical context with a new algorithm for data point removal from progress curves, dubbed iFIT. Although our results suggest that in the context of PD, there is no clinically useful correlation between cognitive status on the one hand and PON1 genetic and enzyme-kinetic parameters on the other hand, this should not discourage future investigation into PON1’s potential associations with other types of dementia.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Toft, P. B., et al.
(författare)
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Microbial metabolite p-cresol inhibits gut hormone expression and regulates small intestinal transit in mice
- 2023
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Ingår i: FRONTIERS IN ENDOCRINOLOGY. - 1664-2392. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- p-cresol is a metabolite produced by microbial metabolism of aromatic amino acid tyrosine. p-cresol and its conjugated forms, p-cresyl sulfate and p-cresyl glucuronide, are uremic toxins that correlate positively with chronic kidney disease and diabetes pathogenesis. However, how p-cresol affects gut hormones is unclear. Here, we expose immortalized GLUTag cells to increasing concentrations of p-cresol and found that p-cresol inhibited Gcg expression and reduced glucagon-like peptide-1 (GLP-1) secretion in vitro. In mice, administration of p-cresol in the drinking water for 2 weeks reduced the transcript levels of Gcg and other gut hormones in the colon; however, it did not affect either fasting or glucose-induced plasma GLP-1 levels. Furthermore, it did not affect glucose tolerance but promoted faster small intestinal transit in mice. Overall, our data suggest that microbial metabolite p-cresol suppresses transcript levels of gut hormones and regulates small intestinal transit in mice.
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| 26. |
- Wen, J, et al.
(författare)
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Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia
- 2023
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 28:21, s. 475-482
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Tidskriftsartikel (refereegranskat)abstract
- Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2–20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.
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| 27. |
- Ahlin, Sofie, 1985, et al.
(författare)
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Metabolite Changes After Metabolic Surgery – Associations to Parameters Reflecting Glucose Homeostasis and Lipid Levels
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To test the hypothesis that adipose tissue gene expression patterns would be affected by metabolic surgery and we aimed to identify genes and metabolic pathways as well as metabolites correlating with metabolic changes following metabolic surgery. Materials and Methods: This observational study was conducted at the Obesity Unit at the Catholic University Hospital of the Sacred Heart in Rome, Italy. Fifteen patients, of which six patients underwent Roux-en-Y gastric bypass and nine patients underwent biliopancreatic diversion, were included. The participants underwent an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Small polar metabolites were analyzed with a two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Gene expression analysis of genes related to metabolism of amino acids and fatty acids were analyzed in subcutaneous adipose tissue. All procedures were performed at study start and at follow-up (after 185.3 ± 72.9 days). Results: Twelve metabolites were significantly changed after metabolic surgery. Six metabolites were identified as 3-indoleacetic acid, 2-hydroxybutyric acid, valine, glutamic acid, 4-hydroxybenzeneacetic acid and alpha-tocopherol. The branched chain amino acids displayed a significant decrease together with a decrease in BCAT1 adipose tissue mRNA levels. Changes in the identified metabolites were associated to changes in lipid, insulin and glucose levels. Conclusions: Our study has identified metabolites and metabolic pathways that are altered by metabolic surgery and may be used as biomarkers for metabolic improvement. Copyright © 2021 Ahlin, Cefalo, Bondia-Pons, Trošt, Capristo, Marini, Romero, Zorzano, Gastaldelli, Mingrone and Nolan.
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| 28. |
- Bauckneht, Matteo, et al.
(författare)
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Associations among education, age, and the dementia with Lewy bodies (DLB) metabolic pattern: A European-DLB consortium project
- 2021
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Ingår i: Alzheimer's & Dementia. - : WILEY. - 1552-5260 .- 1552-5279. ; 17:8, s. 1277-1286
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Tidskriftsartikel (refereegranskat)abstract
- Introduction We assessed the influence of education as a proxy of cognitive reserve and age on the dementia with Lewy bodies (DLB) metabolic pattern. Methods Brain 18F-fluorodeoxyglucose positron emission tomography and clinical/demographic information were available in 169 probable DLB patients included in the European DLB-consortium database. Principal component analysis identified brain regions relevant to local data variance. A linear regression model was applied to generate age- and education-sensitive maps corrected for Mini-Mental State Examination score, sex (and either education or age). Results Age negatively covaried with metabolism in bilateral middle and superior frontal cortex, anterior and posterior cingulate, reducing the expression of the DLB-typical cingulate island sign (CIS). Education negatively covaried with metabolism in the left inferior parietal cortex and precuneus (making the CIS more prominent). Discussion These findings point out the importance of tailoring interpretation of DLB biomarkers considering the concomitant effect of individual, non-disease-related variables such as age and cognitive reserve.
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| 29. |
- Bilkei-Gorzo, Orsolya, et al.
(författare)
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The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection
- 2022
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Ingår i: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075.
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Tidskriftsartikel (refereegranskat)abstract
- Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes. Macrophage activation by interferon gamma (IFN-gamma) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-gamma activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-gamma activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.
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| 30. |
- Breyer, F., et al.
(författare)
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TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria
- 2021
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Ingår i: Embo Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 40:10
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Tidskriftsartikel (refereegranskat)abstract
- Tumour progression locus 2 (TPL-2) kinase mediates Toll-like receptor (TLR) activation of ERK1/2 and p38 alpha MAP kinases in myeloid cells to modulate expression of key cytokines in innate immunity. This study identified a novel MAP kinase-independent regulatory function for TPL-2 in phagosome maturation, an essential process for killing of phagocytosed microbes. TPL-2 catalytic activity was demonstrated to induce phagosome acidification and proteolysis in primary mouse and human macrophages following uptake of latex beads. Quantitative proteomics revealed that blocking TPL-2 catalytic activity significantly altered the protein composition of phagosomes, particularly reducing the abundance of V-ATPase proton pump subunits. Furthermore, TPL-2 stimulated the phosphorylation of DMXL1, a regulator of V-ATPases, to induce V-ATPase assembly and phagosome acidification. Consistent with these results, TPL-2 catalytic activity was required for phagosome acidification and the efficient killing of Staphylococcus aureus and Citrobacter rodentium following phagocytic uptake by macrophages. TPL-2 therefore controls innate immune responses of macrophages to bacteria via V-ATPase induction of phagosome maturation.
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| 31. |
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| 32. |
- Chan, AJS, et al.
(författare)
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Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6463-
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Tidskriftsartikel (refereegranskat)abstract
- Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorize 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We develop a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD have a significantly higher GRVS compared to those with nondysmorphic ASD (P = 0.03). Using the polygenic transmission disequilibrium test, we observe an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P = 2.9 × 10−3). These findings replicate using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.
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| 33. |
- De La Fuente, Alerie Guzman, et al.
(författare)
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Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:8, s. 1755-1764
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Tidskriftsartikel (refereegranskat)abstract
- The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.
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| 34. |
- Etminani, Kobra, 1984-, et al.
(författare)
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A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimers disease, and mild cognitive impairment using brain 18F-FDG PET
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - New York : Springer. - 1619-7070 .- 1619-7089. ; 49, s. 563-584
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimers disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimers disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare models performance to that of multiple expert nuclear medicine physicians readers. Materials and methods Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimers disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The models performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. Results The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. Conclusion Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.
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| 35. |
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| 36. |
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| 37. |
- Mikkelsen, Randi Bonke, et al.
(författare)
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Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and diabetes are associated with inflammation and altered plasma levels of several metabolites, which may be involved in disease progression. Some metabolites can activate G protein-coupled receptors (GPCRs) expressed on immune cells where they can modulate metabolic inflammation. Here, we find that 3-hydroxydecanoate is enriched in the circulation of obese individuals with type 2 diabetes (T2D) compared with nondiabetic controls. Administration of 3-hydroxydecanoate to mice promotes immune cell recruitment to adipose tissue, which was associated with adipose inflammation and increased fasting insulin levels. Furthermore, we demonstrate that 3-hydroxydecanoate stimulates migration of primary human and mouse neutrophils, but not monocytes, through GPR84 and Gαi signaling in vitro. Our findings indicate that 3-hydroxydecanoate is a T2D-associated metabolite that increases inflammatory responses and may contribute to the chronic inflammation observed in diabetes.
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| 38. |
- Soliman, Amira, 1980-, et al.
(författare)
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Adopting transfer learning for neuroimaging : a comparative analysis with a custom 3D convolution neural network model
- 2022
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Ingår i: BMC Medical Informatics and Decision Making. - London : BioMed Central (BMC). - 1472-6947. ; 22, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Background: In recent years, neuroimaging with deep learning (DL) algorithms have made remarkable advances in the diagnosis of neurodegenerative disorders. However, applying DL in different medical domains is usually challenged by lack of labeled data. To address this challenge, transfer learning (TL) has been applied to use state-of-the-art convolution neural networks pre-trained on natural images. Yet, there are differences in characteristics between medical and natural images, also image classification and targeted medical diagnosis tasks. The purpose of this study is to investigate the performance of specialized and TL in the classification of neurodegenerative disorders using 3D volumes of 18F-FDG-PET brain scans. Results: Results show that TL models are suboptimal for classification of neurodegenerative disorders, especially when the objective is to separate more than two disorders. Additionally, specialized CNN model provides better interpretations of predicted diagnosis. Conclusions: TL can indeed lead to superior performance on binary classification in timely and data efficient manner, yet for detecting more than a single disorder, TL models do not perform well. Additionally, custom 3D model performs comparably to TL models for binary classification, and interestingly perform better for diagnosis of multiple disorders. The results confirm the superiority of the custom 3D-CNN in providing better explainable model compared to TL adopted ones. © 2022, The Author(s).
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| 39. |
- Stockbauer, Anna, et al.
(författare)
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Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission
- 2024
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 51:4, s. 1023-1034
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA).Methods FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level.Results Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912).Conclusion Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.
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| 40. |
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| 41. |
- Trost, Kari
(författare)
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A new look at parenting during adolescence : reciprocal interactions in everyday life
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this dissertation I pose the question: Under what conditions are parent-child relationships linked to good, or bad, adolescent adjustment and under what conditions are they not? Study I focused on subjects with multiproblematic adjustment. It was proposed that multiproblematic adjustment in adolescence (as well as in late childhood and early adulthood) has to be seen in terms of individual and family characteristics early in life. The findings confirmed the hypothesis that children characterized by both pre-school conduct problem and poor mother-child relations, later in life showed considerably more problems in different environments than did children with other combinations of conduct problems and mother relations. Studies II-IV aimed at understanding the association between parent-child relationships and adjustment specifically during adolescence. Study II examined how parental trust could be gained, the importance of it, and how it could be linked to adolescent adjustment. Since the trust that parents expressed relative to their children was assumed to be primarily based on the knowledge parents have about their children, three possible sources of parental knowledge were examined (of child’s feelings and concerns, of past delinquency, and of daily activities) along with sources of parental knowledge itself. The results showed that parents’ knowledge of daily activities that came from the child’s spontaneous disclosure was most closely linked to their trust in their child, and parents’ trust, in turn, was associated with good parent-child relations and good adjustment on part of the adolescent. Study III examined how parental control, warmth, and communication in the parent-child relationship are associated with positive and negative adolescent adjustment. Structural equations tests of a theoretical model suggested that the link from parental warmth through parental control to adolescent adjustment was weak compared with the path from parental warmth through child disclosure to adolescent adjustment. Across informants, direct parental control was minimally important, if at all. Study IV examined whether adolescents’ not wanting parental involvement was a normal part of the parent-child relationship during adolescence. It was shown that not wanting parents to be involved generally was a sign of poor adolescent adjustment, even when controlling for problem behaviors and family problems. Person-oriented analyses identified a group of adolescents who wanted low levels of parental involvement, who were normal in terms of family problems and behavior problems and showed evidence of healthy psychological functioning. In view of the small size of this group (11%), and the results from the analyses of linear relations, it was concluded that the combination of adolescents’ desires to manage their own free time and healthy functioning is not as normative as it is normally thought. Overall, the results from these four studies provide a basis for taking a bi-directional approach to understanding the parent-child relationship during adolescence, and in particular examining the child’s active role in his or her development. Furthermore, two new issues were brought up in the present dissertation, 1) a new interpretation of problem aggregation and 2) a new view of the parent-child relationship during adolescence. Directions for future research, practical implications for adolescents, their parents, and the issue of generality are included in the discussion.
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| 42. |
- Trost, Kari, et al.
(författare)
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The Study of Family Context : Examining Its Role for Identity Coherence and Adolescent Adjustment for Swedish Adolescents
- 2020
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Ingår i: Journal of Early Adolescence. - : SAGE Publications. - 0272-4316 .- 1552-5449. ; 40:2, s. 165-196
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Tidskriftsartikel (refereegranskat)abstract
- The present cross-sectional study aimed to examine whether characteristics of the parent-child relationship in adolescence are important for adjustment and identity development. Participants were recruited from schools in central Sweden for a larger longitudinal study when the cohort was 13- to 14-year-olds (N = 3,667). Characteristics of the parent-child relationship, like parental warmth, democratic parenting, and child communication, and adolescent adjustment problems and identity coherence were studied. It was found that democratic parenting was positively linked to child communication but negatively associated with problematic peer relationships and behavioral problems. Parental warmth was linked to other parenting characteristics as well as identity cohesion. Democratic parenting was linked to greater school engagement and identity coherence for boys and girls. Gender differences were found. The findings support the notion that democratic and warm parenting may provide support for adolescent identity development and adjustment.
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| 43. |
- van Kuilenburg, Andre B. P., et al.
(författare)
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Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:15, s. 1433-1441
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Tidskriftsartikel (refereegranskat)abstract
- We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5′ untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.
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| 44. |
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