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| 2. |
- Hammarsjö, A., et al.
(författare)
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High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses
- 2021
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Ingår i: Journal of Human Genetics. - : Springer Nature. - 1434-5161 .- 1435-232X. ; 66:10, s. 995-1008
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.
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| 3. |
- Jacob, P., et al.
(författare)
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Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13
- 2023
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Ingår i: NPJ GENOMIC MEDICINE. - 2056-7944. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.
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| 4. |
- Hammarsjo, A, et al.
(författare)
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Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15585-
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Tidskriftsartikel (refereegranskat)abstract
- The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
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| 5. |
- Girisha, R., et al.
(författare)
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Fusing the navigation information of dual foot-mounted zero-velocity-update-Aided inertial navigation systems
- 2014
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Ingår i: 2014 International Conference on Signal Processing and Communications, SPCOM 2014. - : Institute of Electrical and Electronics Engineers. - 9781479946655
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Konferensbidrag (refereegranskat)abstract
- A range constraint method viz. centroid method is proposed to fuse the navigation information of dual (right and left) foot-mounted Zero-velocity-UPdaTe (ZUPT)-Aided Inertial Navigation Systems (INSs). Here, the range constraint means that the distance of separation between the position estimates of right and left foot ZUPT-Aided INSs cannot be greater than a quantity known as foot-to-foot maximum separation. We present the experimental results which illustrate the applicability of the proposed method. The results show that the proposed method significantly enhances the accuracy of the navigation solution when compared to using two uncoupled foot-mounted ZUPT-Aided INSs. Also, we compare the performance of the proposed method with the existing data fusion methods.
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| 6. |
- Prateek, G. V., et al.
(författare)
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Data fusion of dual foot-mounted INS to reduce the systematic heading drift
- 2013
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Ingår i: Fourth International Conference on Intelligent Systems, Modelling and Simulation (ISMS 2013). - 9780769549637 ; , s. 208-213
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Konferensbidrag (refereegranskat)abstract
- In this report, we investigate the problem of applying a range constraint in order to reduce the systematic heading drift in a foot-mounted inertial navigation system (INS) (motion-tracking). We make use of two foot-mounted INS, one on each foot, which are aided with zero-velocity detectors. A novel algorithm is proposed in order to reduce the systematic heading drift. The proposed algorithm is based on the idea that the separation between the two feet at any given instance must always lie within a sphere of radius equal to the maximum possible spatial separation between the two feet. A Kalman filter, getting one measurement update and two observation updates is used in this algorithm.
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| 7. |
- Turner, Lucy M., et al.
(författare)
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Pathogenic marine microbes influence the effects of climate change on a commercially important tropical bivalve
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- There is growing evidence that climate change will increase the prevalence of toxic algae and harmful bacteria, which can accumulate in marine bivalves. However, we know little about any possible interactions between exposure to these microorganisms and the effects of climate change on bivalve health, or about how this may affect the bivalve toxin-pathogen load. In mesocosm experiments, mussels, Perna viridis, were subjected to simulated climate change (warming and/or hyposalinity) and exposed to harmful bacteria and/or toxin-producing dinoflagellates. We found significant interactions between climate change and these microbes on metabolic and/or immunobiological function and toxin-pathogen load in mussels. Surprisingly, however, these effects were virtually eliminated when mussels were exposed to both harmful microorganisms simultaneously. This study is the first to examine the effects of climate change on determining mussel toxin-pathogen load in an ecologically relevant, multi-trophic context. The results may have considerable implications for seafood safety.
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| 8. |
- Turner, Lucy M., et al.
(författare)
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Toxic Algae Silence Physiological Responses to Multiple Climate Drivers in a Tropical Marine Food Chain
- 2019
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Research on the effects of climate change in the marine environment continues to accelerate, yet we know little about the effects of multiple climate drivers in more complex, ecologically relevant settings - especially in sub-tropical and tropical systems. In marine ecosystems, climate change (warming and freshening from land run-oft) will increase water column stratification which is favorable for toxin producing dinoflagellates. This can increase the prevalence of toxic microalgal species, leading to bioaccumulation of toxins by filter feeders, such as bivalves, with resultant negative impacts on physiological performance. In this study we manipulated multiple climate drivers (warming, freshening, and acidification), and the availability of toxic microalgae, to determine their impact on the physiological health, and toxin load of the tropical filter-feeding clam, Meretrix meretrix. Using a structural equation modeling (SEM) approach, we found that exposure to projected marine climates resulted in direct negative effects on metabolic and immunological function and, that these effects were often more pronounced in clams exposed to multiple, rather than single climate drivers. Furthermore, our study showed that these physiological responses were modified by indirect effects mediated through the food chain. Specifically, we found that when bivalves were fed with a toxin-producing dinoflagellate (Alexandrium minutum) the physiological responses, and toxin load changed differently and in a non-predictable way compared to clams exposed to projected marine climates only. Specifically, oxygen consumption data revealed that these clams did not respond physiologically to climate warming or the combined effects of warming, freshening and acidification. Our results highlight the importance of quantifying both direct and, indirect food chain effects of climate drivers on a key tropical food species, and have important implications for shellfish production and food safety in tropical regions.
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