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- Helbig, K. L., et al.
(författare)
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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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| 2. |
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| 3. |
- Stern, R.J., et al.
(författare)
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Cadomian (∼560 Ma) crust buried beneath the northern Arabian Peninsula: Mineral, chemical, geochronological, and isotopic constraints from NE Jordan xenoliths.
- 2016
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 0012-821X .- 1385-013X. ; 436, s. 31-42
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Tidskriftsartikel (refereegranskat)abstract
- In order to better understand the nature and formation of the lower continental crust beneath northern Arabia, we studied lower crustal xenoliths brought up by Neogene basalts in NE Jordan. Most of these xenoliths are comprised of primary phases plagioclase + two-pyroxenes with magnetite and ilmenite. Most clinopyroxene are augite whereas orthopyroxene mostly are hypersthene (Mg# = 50–80). Plagioclase feldspar is dominantly andesine–labradorite; pyrope-rich garnet and Fe-rich olivine (Fo75 to Fo62) are rare. These xenoliths represent cumulates formed from intermediate magmas that pooled in the lower crust. Many xenoliths also contain small, fine-grained K-rich zones interpreted as melt pockets reflecting late magmatic infiltration of the lower crust. The xenoliths display a wide range in major element compositions (37–51 wt.% SiO2, 4–15 wt.% MgO and 0.1–6.3 wt.% TiO2), enrichment in Ba, K, Sr, Pb and Eu, and some trace element ratios atypical of bulk continental crust (e.g., K/Rb=1265±565, K/U=63000±60080 and Th/U=0.96±0.56); these extreme ratios reflect widespread K-metasomatism associated with melt pockets. The magmas from which these cumulates formed may have been generated at a reararc convergent margin setting. Four U–Pb zircon populations yield indistinguishable ages of 554±4 Ma; 559±5 Ma; 559±6 Ma, and 563±5 Ma. Initial 87Sr/86Sr values (0.70260–0.70352) and positive εNd(560)εNd(560) (with the exception of a single, more radiogenic sample (+9.6), range=+1.3 to +4.8) indicate that the lower crust sampled by the xenoliths originated in the asthenospheric mantle, with little or no interaction with older crust, although Pb isotopic compositions allow for some interaction with older or subducted crustal materials. We interpret the geochemistry and mineralogy of these xenoliths to indicate that the lower crust beneath NE Jordan is mafic and comprised of plagioclase-rich 2-pyroxene igneous rocks. The lower crust of this area formed by magmatic underplating over less than 18 Ma. The crust of NE Jordan is significantly younger than the crust of the northernmost Arabian–Nubian Shield and represents a fragment of Cadomian (600–520 Ma) crust that may make up the NE margin of the Arabian Plate.
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