Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
- MeSH
- draslíkové kanály Shab genetika MeSH
- kineziny genetika MeSH
- kojenec MeSH
- křeče u dětí diagnóza genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- předškolní dítě MeSH
- proteiny přenášející monosacharidy genetika MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go genetika MeSH
- receptory cytoplazmatické a nukleární genetika MeSH
- represorové proteiny genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pollination in flowering plants is initiated by germination of pollen grains on stigmas followed by fast growth of pollen tubes representing highly energy-consuming processes. The symplastic isolation of pollen grains and tubes requires import of Suc available in the apoplast. We show that the functional coupling of Suc cleavage by invertases and uptake of the released hexoses by monosaccharide transporters are critical for pollination in tobacco (Nicotiana tabacum). Transcript profiling, in situ hybridization, and immunolocalization of extracellular invertases and two monosaccharide transporters in vitro and in vivo support the functional coupling in supplying carbohydrates for pollen germination and tube growth evidenced by spatiotemporally coordinated expression. Detection of vacuolar invertases in maternal tissues by these approaches revealed metabolic cross talk between male and female tissues and supported the requirement for carbohydrate supply in transmitting tissue during pollination. Tissue-specific expression of an invertase inhibitor and addition of the chemical invertase inhibitor miglitol strongly reduced extracellular invertase activity and impaired pollen germination. Measurements of (competitive) uptake of labeled sugars identified two import pathways for exogenously available Suc into the germinating pollen operating in parallel: direct Suc uptake and via the hexoses after cleavage by extracellular invertase. Reduction of extracellular invertase activity in pollen decreases Suc uptake and severely compromises pollen germination. We further demonstrate that Glc as sole carbon source is sufficient for pollen germination, whereas Suc is supporting tube growth, revealing an important regulatory role of both the invertase substrate and products contributing to a potential metabolic and signaling-based multilayer regulation of pollination by carbohydrates.
- MeSH
- 1-deoxynojirimycin analogy a deriváty farmakologie MeSH
- biologické modely MeSH
- hexosy metabolismus MeSH
- inhibitory enzymů farmakologie MeSH
- invertasa antagonisté a inhibitory metabolismus MeSH
- klíčení účinky léků MeSH
- opylení účinky léků MeSH
- proteiny přenášející monosacharidy genetika metabolismus MeSH
- pylová láčka účinky léků enzymologie růst a vývoj MeSH
- regulace genové exprese u rostlin účinky léků MeSH
- reprodukovatelnost výsledků MeSH
- rostlinné proteiny genetika metabolismus MeSH
- sacharidy farmakologie MeSH
- tabák enzymologie genetika metabolismus fyziologie MeSH
- Publikační typ
- časopisecké články MeSH
Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces CSR2 transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.
- MeSH
- arrestin genetika metabolismus MeSH
- časové faktory MeSH
- endocytóza * MeSH
- genetická transkripce MeSH
- glukosa nedostatek MeSH
- jaderné proteiny genetika metabolismus MeSH
- mutace MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteinfosfatasa 1 metabolismus MeSH
- proteinkinasy závislé na cyklickém AMP metabolismus MeSH
- proteiny 14-3-3 metabolismus MeSH
- proteiny přenášející monosacharidy genetika metabolismus MeSH
- regulace genové exprese u hub MeSH
- represorové proteiny metabolismus MeSH
- Saccharomyces cerevisiae - proteiny genetika metabolismus MeSH
- Saccharomyces cerevisiae genetika metabolismus MeSH
- ubikvitinace MeSH
- Publikační typ
- časopisecké články MeSH
Phospholipase C (Plc1p) in Saccharomyces cerevisiae is required for normal degradation of repressor Mth1p and expression of the HXT genes encoding cell membrane transporters of glucose. Plc1p is also required for normal localization of glucose transporters to the cell membrane. Consequently, plc1Δ cells display histone hypoacetylation and transcriptional defects due to reduced uptake and metabolism of glucose to acetyl-CoA, a substrate for histone acetyltransferases. In the presence of glucose, Mth1p is phosphorylated by casein kinase I Yck1/2p, ubiquitinated by the SCFGrr1 complex and degraded by the proteasome. Here, we show that while Plc1p does not affect the function of the SCFGrr1 complex or the proteasome, it is required for normal protein level of Yck2p. Since stability of Yck1/2p is regulated by a glucose-dependent mechanism, PLC1 inactivation results in destabilization of Yck1/2p and defect in Mth1p degradation. Based on our results and published data, we propose a model in which plc1Δ mutation causes increased internalization of glucose transporters, decreased transport of glucose into the cells, and consequently decreased stability of Yck1/2p, increased stability of Mth1p and decreased expression of the HXT genes.
- MeSH
- fosfolipasy typu C metabolismus MeSH
- kasein kinasa I chemie metabolismus MeSH
- proteiny přenášející monosacharidy genetika metabolismus MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- Saccharomyces cerevisiae - proteiny chemie metabolismus MeSH
- Saccharomyces cerevisiae cytologie genetika metabolismus MeSH
- stabilita enzymů MeSH
- Publikační typ
- časopisecké články MeSH
Transporter genes and cytokinins are key targets for crop improvement. These genes are active during the development of the seed and its establishment as a strong sink. However, during germination, the seed transitions to being a source for the developing root and shoot. To determine if the sucrose transporter (SUT), amino acid permease (AAP), Sugar Will Eventually be Exported Transporter (SWEET), cell wall invertase (CWINV), cytokinin biosynthesis (IPT), activation (LOG) and degradation (CKX) gene family members are involved in both the sink and source activities of seeds, we used RT-qPCR to determine the expression of multiple gene family members, and LC-MS/MS to ascertain endogenous cytokinin levels in germinating Pisum sativum L. We show that genes that are actively expressed when the seed is a strong sink during its development, are also expressed when the seed is in the reverse role of being an active source during germination and early seedling growth. Cytokinins were detected in the imbibing seeds and were actively biosynthesised during germination. We conclude that, when the above gene family members are targeted for seed yield improvement, a downstream effect on subsequent seed germination or seedling vigour must be taken into consideration.
- MeSH
- buněčná stěna enzymologie MeSH
- cytokininy biosyntéza genetika MeSH
- hrách setý genetika růst a vývoj MeSH
- invertasa biosyntéza genetika MeSH
- klíčení genetika MeSH
- proteiny přenášející monosacharidy biosyntéza genetika MeSH
- regulace genové exprese u rostlin MeSH
- regulátory růstu rostlin genetika MeSH
- semena rostlinná genetika růst a vývoj MeSH
- semenáček genetika MeSH
- tandemová hmotnostní spektrometrie MeSH
- transportní systémy aminokyselin biosyntéza genetika MeSH
- Publikační typ
- časopisecké články MeSH
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10(-8)) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10(-11); ATG13-AMBRA1, P = 6.7 × 10(-10); AHI1, P = 8.4 × 10(-10); CLEC16A, P = 1.4 × 10(-9)) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3(+) regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- celogenomová asociační studie MeSH
- deficience IgA genetika MeSH
- genetická variace * MeSH
- genové regulační sítě MeSH
- kohortové studie MeSH
- lektiny typu C genetika MeSH
- lidé MeSH
- proteiny přenášející monosacharidy genetika MeSH
- proteiny spojené s autofagií genetika MeSH
- RNA dlouhá nekódující genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
Transport across the plasma membrane is the first step at which nutrient supply is tightly regulated in response to intracellular needs and often also rapidly changing external environment. In this review, I describe primarily our current understanding of multiple interconnected glucose-sensing systems and signal-transduction pathways that ensure fast and optimum expression of genes encoding hexose transporters in three yeast species, Saccharomyces cerevisiae, Kluyveromyces lactis and Candida albicans. In addition, an overview of GAL- and MAL-specific regulatory networks, controlling galactose and maltose utilization, is provided. Finally, pathways generating signals inducing posttranslational degradation of sugar transporters will be highlighted.
- MeSH
- genové regulační sítě genetika MeSH
- kvasinky genetika metabolismus fyziologie MeSH
- proteiny přenášející monosacharidy genetika metabolismus MeSH
- regulace genové exprese u hub * MeSH
- signální transdukce * MeSH
- životní prostředí MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
