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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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- Vonk, J. E., et al.
(författare)
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Reviews and syntheses : Effects of permafrost thaw on Arctic aquatic ecosystems
- 2015
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 12:23, s. 7129-7167
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Tidskriftsartikel (refereegranskat)abstract
- The Arctic is a water-rich region, with freshwater systems covering about 16% of the northern permafrost landscape. Permafrost thaw creates new freshwater ecosystems, while at the same time modifying the existing lakes, streams, and rivers that are impacted by thaw. Here, we describe the current state of knowledge regarding how permafrost thaw affects lentic (still) and lotic (moving) systems, exploring the effects of both thermokarst (thawing and collapse of ice-rich permafrost) and deepening of the active layer (the surface soil layer that thaws and refreezes each year). Within thermokarst, we further differentiate between the effects of thermokarst in lowland areas vs. that on hillslopes. For almost all of the processes that we explore, the effects of thaw vary regionally, and between lake and stream systems. Much of this regional variation is caused by differences in ground ice content, topography, soil type, and permafrost coverage. Together, these modifying factors determine (i) the degree to which permafrost thaw manifests as thermokarst, (ii) whether thermokarst leads to slumping or the formation of thermokarst lakes, and (iii) the manner in which constituent delivery to freshwater systems is altered by thaw. Differences in thaw-enabled constituent delivery can be considerable, with these modifying factors determining, for example, the balance between delivery of particulate vs. dissolved constituents, and inorganic vs. organic materials. Changes in the composition of thaw-impacted waters, coupled with changes in lake morphology, can strongly affect the physical and optical properties of thermokarst lakes. The ecology of thaw-impacted lakes and streams is also likely to change; these systems have unique microbiological communities, and show differences in respiration, primary production, and food web structure that are largely driven by differences in sediment, dissolved organic matter, and nutrient delivery. The degree to which thaw enables the delivery of dissolved vs. particulate organic matter, coupled with the composition of that organic matter and the morphology and stratification characteristics of recipient systems will play an important role in determining the balance between the release of organic matter as greenhouse gases (CO2 and CH4), its burial in sediments, and its loss downstream. The magnitude of thaw impacts on northern aquatic ecosystems is increasing, as is the prevalence of thaw-impacted lakes and streams. There is therefore an urgent need to quantify how permafrost thaw is affecting aquatic ecosystems across diverse Arctic landscapes, and the implications of this change for further climate warming.
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