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Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.
- MeSH
- dánio pruhované embryologie genetika MeSH
- dítě MeSH
- embryo nesavčí MeSH
- fibroblasty metabolismus MeSH
- fosfatidylseriny biosyntéza genetika MeSH
- hyperostóza MeSH
- kultivované buňky MeSH
- lidé MeSH
- mladiství MeSH
- mnohočetné abnormality genetika MeSH
- molekulární sekvence - údaje MeSH
- mutace * MeSH
- nanismus MeSH
- syndrom MeSH
- transferasy dusíkatých skupin genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- autoprotilátky analýza MeSH
- dospělí MeSH
- erytrocyty fyziologie imunologie patologie MeSH
- fosfatidylseriny krev MeSH
- lidé MeSH
- psychosomatické poruchy farmakoterapie krev MeSH
- purpura farmakoterapie krev psychologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Phosphatidylserine (PS) in quiescent cells is predominantly confined to the inner leaflet of the plasma membrane. Externalization of PS is a marker of apoptosis, exocytosis, and some nonapoptotic activation events. It has been proposed that PS externalization is regulated by the activity of PLSCR1 (phospholipid scramblase 1), a Ca(2+)-dependent endofacial plasma membrane protein, which is tyrosine-phosphorylated in activated cells. It is, however, unclear how the phosphorylation of PLSCR1 is related to its membrane topography, PS externalization, and exocytosis. Using rat basophilic leukemia cells as a model, we show that nonapoptotic PS externalization induced through the high affinity IgE receptor (FcepsilonRI) or the glycosylphosphatidylinositol-anchored protein Thy-1 does not correlate with enhanced tyrosine phosphorylation of PLSCR1. In addition, PS externalization in FcepsilonRI- or Thy-1-activated cells is not associated with alterations of PLSCR1 fine topography as detected by electron microscopy on isolated plasma membrane sheets. In contrast, activation by calcium ionophore A23187 induces changes in the cellular distribution of PLSCR1. We also show for the first time that in pervanadate-activated cells, exocytosis occurs even in the absence of PS externalization. Finally, we document here that tyrosine-phosphorylated PLSCR1 is preferentially located in detergent-insoluble membranes, suggesting its involvement in the formation of membrane-bound signaling assemblies. The combined data indicate that changes in the topography of PLSCR1 and its tyrosine phosphorylation, PS externalization, and exocytosis are independent phenomena that could be distinguished by employing specific conditions of activation.
- MeSH
- biologické modely MeSH
- buněčná membrána metabolismus MeSH
- calcimycin farmakologie MeSH
- detergenty farmakologie MeSH
- exocytóza MeSH
- financování organizované MeSH
- fosfatidylseriny chemie MeSH
- fosforylace MeSH
- inhibitory enzymů farmakologie MeSH
- ionofory farmakologie MeSH
- konfokální mikroskopie MeSH
- krysa rodu rattus MeSH
- nádorové buněčné linie MeSH
- proteiny přenášející fosfolipidy metabolismus MeSH
- tyrosin chemie MeSH
- vanadáty farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
Low-density lipoprotein (LDL) modifications and platelet activation are major risk factors for cardiovascular diseases. When platelets are exposed to oxidative stress, they become activated. Oxidized LDL (ox-LDL) and metal-catalysed oxidation systems such as Fe3+/ascorbic acid increase free radical production. We wanted to verify whether melatonin has a protective effect against oxidative modifications and phosphatidylserine externalization in platelets induced by ox-LDL and Fe3+/ascorbic acid. For in vitro effects of melatonin on platelets, ADPactivated platelets were incubated with ox-LDL or Fe3+/ascorbic acid for 1 h at 37 oC with or without melatonin. Then platelet malondialdehyde, protein carbonyl and glutathione levels were measured. Platelet phosphatidylserine exposure was measured with annexin-V using flow cytometry. Malondialdehyde, protein carbonyl and phosphatidylserine levels of platelets treated with Fe3+/ascorbic acid significantly increased compared to the control group. Glutathione contents of Fe3+/ascorbic acid-treated platelets significantly decreased. Melatonin pre-treatment of Fe3+/ascorbic acid-treated platelets caused a mar ked reduction in malondialdehyde and phosphatidylserine levels and a marked increase in glutathione levels. Melatonin also caused non-significant reduction in protein carbonyl contents of Fe3+/ascorbic acid-treated platelets. Malondialdehyde, protein carbonyl and phosphatidylserine levels of platelets treated with ox-LDL also significantly increased compared to the control group. Platelet glutathione levels non-significantly decreased with ox-LDL. With addition of melatonin, malondialdehyde, protein carbonyl and phosphatidylserine levels of platelets treated with ox-LDL significantly decreased. These data suggest that melatonin may protect platelets from iron overload-induced and ox-LDL-induced oxidative modifications and also from the triggering signals of apoptosis activation, possibly due to its scavenger effect on toxic free radicals.
- MeSH
- antioxidancia farmakologie metabolismus MeSH
- dospělí MeSH
- fosfatidylseriny metabolismus MeSH
- glutathion metabolismus MeSH
- kyselina askorbová farmakologie MeSH
- lidé MeSH
- lipoproteiny LDL farmakologie MeSH
- malondialdehyd metabolismus MeSH
- melatonin farmakologie MeSH
- oxidace-redukce účinky léků MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- trombocyty metabolismus účinky léků MeSH
- železité sloučeniny farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
Analysis of c-myb gene down-regulation in differentiating C212 cells revealed that in proliferating cells, c-myb expression is high and ceases as the proliferation rate decreases. However, a low level of c-myb mRNA was detected in confluent non-proliferating differentiating cells for an extended period of time before it declined to an undetectable level. The time course of c-myb gene silencing in differentiating cells correlated with exposition of phosphatidylserine (PS) on the cell surface. Moreover, the interaction of exposed PS with exogenously added annexin V perturbed PS-mediated cell signaling and transiently up-regulated the declining c-myb expression. We, therefore, suggest that cell surface-exposed PS, which plays a role in the process of myotube formation, is also involved in the down-regulation of c-myb expression.
- MeSH
- annexin A5 metabolismus MeSH
- buněčná diferenciace MeSH
- buněčné linie MeSH
- DNA primery MeSH
- financování organizované MeSH
- fluorescenční protilátková technika MeSH
- fosfatidylseriny metabolismus MeSH
- messenger RNA genetika MeSH
- myši MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- protoonkogenní proteiny c-myb genetika MeSH
- sekvence nukleotidů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH