| 1. |
- Hu, H., et al.
(författare)
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X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:1, s. 133-148
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Tidskriftsartikel (refereegranskat)abstract
- X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
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| 2. |
- Chu, M.S., et al.
(författare)
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Physics of Plasmas Modeling of Feedback and Rotation Stabilization of the Resistive Wall Mode in Tokamaks
- 2004
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Ingår i: Physics of Plasmas. ; 11, s. 2497-
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Tidskriftsartikel (refereegranskat)abstract
- Steady-state operation of the advanced tokamak reactor relies on maintaining plasma stability with respect to the resistive wall mode ~RWM!. Active magnetic feedback and plasma rotation are the two methods proposed and demonstrated for this purpose. A comprehensive modeling effort including both magnetic feedback and plasma rotation is needed for understanding the physical mechanisms of the stabilization and to project to future devices. For plasma with low rotation, a complete solution for the feedback issue is obtained by assuming the plasma obeys ideal magnetohydrodynamics ~MHDs! and utilizing a normal mode approach ~NMA! @M. S. Chu et al., Nucl. Fusion 43, 441 ~2003!#. It is found that poloidal sensors are more effective than radial sensors and coils inside of the vacuum vessel more effective than outside. For plasmas with non-negligible rotation, a comprehensive linear nonideal MHD code, the MARS-F has been found to be suitable. MARS-F @Y. Q. Liu et al., Phys. Plasmas 7, 3681 ~2000!# has been benchmarked in the ideal MHD limit against the NMA. The effect of rotation stabilization of the plasma depends on the plasma dissipation model. Broad qualitative features of the experiment are reproduced. Rotation reduces the feedback gain required for RWM stabilization. Reduction is significant when rotation is near the critical rotation speed needed for stabilization. The International Thermonuclear Experimental Reactor ~ITER! @R. Aymar et al., Plasma Phys. Controlled Fusion 44, 519 ~2002!# ~scenario IV for advanced tokamak operation! may be feedback stabilized with babove the no wall limit and up to an increment of ;50% towards the ideal limit. Rotation further improves the stability.
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| 3. |
- Molin, Anna-Maja, et al.
(författare)
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A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features
- 2012
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:2, s. 104-109
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Tidskriftsartikel (refereegranskat)abstract
- Background Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype. phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. Methods Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. Results The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype. phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. Conclusion A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.
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| 4. |
- Okabayashi, M., et al.
(författare)
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Control of the resistive wall mode with internal coils in the DIII-D tokamak
- 2005
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 45:12, s. 1715-1731
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Tidskriftsartikel (refereegranskat)abstract
- Internal coils, 'I-Coils', were installed inside the vacuum vessel of the DIII-D device to generate non-axisymmetric magnetic fields to act directly on the plasma. These fields are predicted to stabilize the resistive wall mode (RWM) branch of the long-wavelength external kink mode with plasma beta close to the ideal wall limit. Feedback using these I-Coils was found to be more effective as compared to using external coils located outside the vacuum vessel. Locating the coils inside the vessel allows for a faster response and the coil geometry also allows for better coupling to the helical mode structure. Initial results were reported previously (Strait E.J. et al 2004 Phys. Plasmas 11 2505). This paper reports on results from extended feedback stabilization operations, achieving plasma parameters up to the regime of Cβ ≈ 1.0 and open loop growth rates of γopenτw ≳ 25 where the RWM was predicted to be unstable with only the 'rotational viscous stabilization mechanism'. Here Cβ ≈ (β - βno-wall.limit)/(βideal.wall.limit - βno-wall.limit) is a measure of the beta relative to the stability limits without a wall and with a perfectly conducting wall, and τw is the resistive flux penetration time of the wall. These feedback experimental results clarified the processes of dynamic error field correction and direct RWM stabilization, both of which took place simultaneously during RWM feedback stabilization operation. MARS-F modelling provides a critical rotation velocity in reasonable agreement with the experiment and predicts that the growth rate increases rapidly as rotation decreases below the critical. The MARS-F code also predicted that for successful RWM magnetic feedback, the characteristic time of the power supply should be limited to a fraction of the growth time of the targeted RWM. The possibility of further improvements in the presently achievable range of operation of feedback gain values is also discussed.
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| 5. |
- Johansson, J., et al.
(författare)
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Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions
- 2024
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Ingår i: European Journal of Human Genetics. - : SPRINGERNATURE. - 1018-4813 .- 1476-5438. ; 32:3, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.
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| 6. |
- Sabbagh, S. A., et al.
(författare)
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Resistive wall stabilized operation in rotating high beta NSTX plasmas
- 2006
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 46:5, s. 635-644
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Tidskriftsartikel (refereegranskat)abstract
- The National Spherical Torus Experiment (NSTX) has demonstrated the advantages of low aspect ratio geometry in accessing high toroidal and normalized plasma beta, and βN ≡ 10 8〈βt〉 aB0/Ip. Experiments have reached βt = 39% and βN = 7.2 through boundary and profile optimization. High βN plasmas can exceed the ideal no-wall stability limit, βNno-wall, for periods much greater than the wall eddy current decay time. Resistive wall mode (RWM) physics is studied to understand mode stabilization in these plasmas. The toroidal mode spectrum of unstable RWMs has been measured with mode number n up to 3. The critical rotation frequency of Bondeson-Chu, Ωcrit = ωA/(4q2), describes well the RWM stability of NSTX plasmas when applied over the entire rotation profile and in conjunction with the ideal stability criterion. Rotation damping and global rotation collapse observed in plasmas exceeding βNno-wall differs from the damping observed during tearing mode activity and can be described qualitatively by drag due to neoclassical toroidal viscosity in the helically perturbed field of an ideal displacement. Resonant field amplification of an applied n = 1 field perturbation has been measured and increases with increasing βN. Equilibria are reconstructed including measured ion and electron pressure, toroidal rotation and flux isotherm constraint in plasmas with core rotation ω/ωA up to 0.48. Peak pressure shifts of 18% of the minor radius from the magnetic axis have been reconstructed.
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| 7. |
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| 8. |
- Flex, Elisabetta, et al.
(författare)
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Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:16, s. 4315-4327
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Tidskriftsartikel (refereegranskat)abstract
- RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
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| 9. |
- Konings, A., et al.
(författare)
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Candidate gene association study for noise-induced hearing loss in two independent noise-exposed populations
- 2009
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Ingår i: Annals of Human Genetics. - : Wiley. - 0003-4800 .- 1469-1809. ; 73:2, s. 215-224
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Tidskriftsartikel (refereegranskat)abstract
- Millions of people are daily exposed to high levels of noise. Consequently, noise-induced hearing loss (NIHL) is one of the most important occupational health hazards worldwide. In this study, we performed an association study for NIHL based on a candidate gene approach. 644 Single Nucleotide Polymorphisms (SNPs) in 53 candidate genes were analyzed in two independent NIHL sample sets, a Swedish set and part of a Polish set. Eight SNPs with promising results were selected and analysed in the remaining part of the Polish samples. One SNP in PCDH15 (rs7095441), resulted in significant associations in both sample sets while two SNPs in MYH14 (rs667907 and rs588035), resulted in significant associations in the Polish sample set and significant interactions with noise exposure level in the Swedish sample set. Calculation of odds ratios revealed a significant association of rs588035 with NIHL in the Swedish high noise exposure level group. Our studies suggest that PCDH15 and MYH14 may be NIHL susceptibility genes, but further replication in independent sample sets is mandatory.
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| 10. |
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