| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
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| 6. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 10. |
- Haas, Brian J., et al.
(författare)
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Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7262, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- Phytophthora infestans is the most destructive pathogen of potato and a model organism for the oomycetes, a distinct lineage of fungus-like eukaryotes that are related to organisms such as brown algae and diatoms. As the agent of the Irish potato famine in the mid-nineteenth century, P. infestans has had a tremendous effect on human history, resulting in famine and population displacement(1). To this day, it affects world agriculture by causing the most destructive disease of potato, the fourth largest food crop and a critical alternative to the major cereal crops for feeding the world's population(1). Current annual worldwide potato crop losses due to late blight are conservatively estimated at $6.7 billion(2). Management of this devastating pathogen is challenged by its remarkable speed of adaptation to control strategies such as genetically resistant cultivars(3,4). Here we report the sequence of the P. infestans genome, which at similar to 240 megabases (Mb) is by far the largest and most complex genome sequenced so far in the chromalveolates. Its expansion results from a proliferation of repetitive DNA accounting for similar to 74% of the genome. Comparison with two other Phytophthora genomes showed rapid turnover and extensive expansion of specific families of secreted disease effector proteins, including many genes that are induced during infection or are predicted to have activities that alter host physiology. These fast-evolving effector genes are localized to highly dynamic and expanded regions of the P. infestans genome. This probably plays a crucial part in the rapid adaptability of the pathogen to host plants and underpins its evolutionary potential.
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| 11. |
- Grenville-Briggs, Laura J., et al.
(författare)
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Cellulose synthesis in Phytophthora infestans is required for normal appressorium formation and successful infection of potato
- 2008
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Ingår i: The Plant Cell. - : Oxford University Press (OUP). - 1040-4651 .- 1532-298X. ; 20:3, s. 720-738
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Tidskriftsartikel (refereegranskat)abstract
- Cellulose, the important structural compound of cell walls, provides strength and rigidity to cells of numerous organisms. Here, we functionally characterize four cellulose synthase genes (CesA) in the oomycete plant pathogen Phytophthora infestans, the causal agent of potato (Solanum tuberosum) late blight. Three members of this new protein family contain Pleckstrin homology domains and form a distinct phylogenetic group most closely related to the cellulose synthases of cyanobacteria. Expression of all four genes is coordinately upregulated during pre- and early infection stages of potato. Inhibition of cellulose synthesis by 2,6-dichlorobenzonitrile leads to a dramatic reduction in the number of normal germ tubes with appressoria, severe disruption of the cell wall in the preinfection structures, and a complete loss of pathogenicity. Silencing of the entire gene family in P. infestans with RNA interference leads to a similar disruption of the cell wall surrounding appressoria and an inability to form typical functional appressoria. In addition, the cellulose content of the cell walls of the silenced lines is >50% lower than in the walls of the nonsilenced lines. Our data demonstrate that the isolated genes are involved in cellulose biosynthesis and that cellulose synthesis is essential for infection by P. infestans.
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| 12. |
- Solaki, Maria, et al.
(författare)
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Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia
- 2022
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:7, s. 832-858
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Tidskriftsartikel (refereegranskat)abstract
- Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying “likely disease-causing” variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as “likely disease-causing” according to ACMG/AMP criteria. We report 48 novel “likely disease-causing” variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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| 13. |
- Branham, Kari, et al.
(författare)
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Mutations in RPGR and RP2 Account for 15% of Males with Simplex Retinal Degenerative Disease
- 2012
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 53:13, s. 8232-8237
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2. METHODS. Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. RESULTS. We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region). CONCLUSIONS. This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. (Invest Ophthalmol Vis Sci. 2012;53:8232-8237) DOI:10.1167/iovs.12-11025
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| 14. |
- Jimenez Berrocoso, Alvaro, et al.
(författare)
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The Lindi Formation (upper Albian-Coniacian) and Tanzania Drilling Project Sites 36-40 (Lower Cretaceous to Paleogene) : Lithostratigraphy, biostratigraphy and chemostratigraphy
- 2015
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Ingår i: Journal of African earth sciences. - : Elsevier BV. - 1464-343X. ; 101, s. 282-308
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Tidskriftsartikel (refereegranskat)abstract
- The 2009 Tanzania Drilling Project (TDP) expedition to southeastern Tanzania cored a total of 572.3 m of sediments at six new mid-Cretaceous to mid-Paleocene boreholes (TDP Sites 36, 37, 38, 39, 40A, 40B). Added to the sites drilled in 2007 and 2008, the new boreholes confirm the common excellent preservation of planktonic and benthic foraminifera and calcareous nannofossils from core samples that will be used for biostratigraphy, evolutionary studies, paleoceanography and climatic reconstructions from the Tanzanian margin, with implications elsewhere. The new sites verify the presence of a relatively expanded Upper Cretaceous succession in the region that has allowed a new stratigraphic unit, named here as the Lindi Formation (Fm), to be formally defined. The Lindi Fm (upper Albian to Coniacian), extending similar to 120 km between Kilwa and Lindi, comprises a 335-m-thick, outer-shelf to upper-slope unit, consisting of dark gray claystone and siltstone interbeds, common finely-laminated intervals, minor cm-thick sandstones and up to 2.6% organic carbon in the Turonian. A subsurface, composite stratotype section is proposed for the Lindi Fm, with a gradational top boundary with the overlying Nangurukuru Fm (Santonian to Maastrichtian) and a sharp bottom contact with underlying upper Albian sandstones. The section cored at TDP Sites 36 and 38 belongs to the Lindi Fm and are of lower to middle Turonian age (planktonic foraminifera Whiteinella archaeocretacea to Helvetoglobotruncana helvetica Zones and nannofossils subzones UC6b +/- UC7). The lower portion of TDP Site 39 (uppermost part of the Lindi Fm) is assigned to the lower to upper Coniacian (planktonic foraminifera Dicarinella concavata Zone and nannofossils zone UC 10), while the remaining part of this site is attributed to the Coniacian-Santonian transition and younger Santonian (planktonic foraminifera D. asymetrica Zone and upper part of nannofossils zone UC10). TDP Site 37 recovered relatively expanded (150 m thick), monotonous calcareous claystones from the lower to upper Maastrichtian (planktonic foraminifera Pseudoguembelina palpebra to Abathomphalus mayaroensis Zones and nannofossils zones UC19 to UC20a(TP)) that were separated by a hiatus and/or a faulted contact from overlying brecciated carbonates of the Selandian (middle Paleocene: PF Zone P3 and nannofossil zone NP5). The lower portion of TDP Sites 40A and 40B recovered sandstones and conglomerates barren of microfossils. Their overlying parts were assigned to incomplete sections of the nannofossil zones NC6A to NC8 (uppermost Barremian to lower Albian). Benthic foraminiferal assemblages allowed the Barremian to lower Aptian to be identified in TDP Sites 40A and 40B, while the upper Aptian to middle Albian (Hedbergella trocoidea to Ticinella primula Zones) were assigned using planktonic foraminifera. Cores recovered at TDP 39 (Coniacian-Santonian) and at TDP Sites 40A and 40B (Barremian-middle Albian) represent the first time that these two intervals have been continuously cored and publicly documented in Tanzania. Bulk sediment isotope records generated for the new sites show lower delta O-18(carb) values in the Turonian and Santonian (similar to-3.5 parts per thousand to -5 parts per thousand) than in the Maastrichtian (similar to-3 parts per thousand), a situation consistent with extreme global warmth in the older intervals and cooling toward the end of the Cretaceous. Also, similar to Turonian sites from previous TDP expeditions, a negative delta C-13(org) excursion was detected across the W. archaeocretacea-H. helvetica boundary of TDP Site 36 (close to, but above, the Cenomanian-Turonian boundary). This excursion probably responded to local processes in the region, but it is unknown whether they were related to the recovery phase from Ocean Anoxic Event 2.
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