Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular "clamp" formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spectroscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W mutation prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.
- MeSH
- abnormální erytrocyty MeSH
- aminokyseliny metabolismus MeSH
- dyslexie MeSH
- endoplazmatické retikulum metabolismus MeSH
- ichtyóza MeSH
- kanály aktivované uvolněním vápníku * genetika MeSH
- membránové proteiny * metabolismus MeSH
- migréna MeSH
- mióza MeSH
- mutace MeSH
- myši MeSH
- protein ORAI1 metabolismus MeSH
- protein STIM1 genetika MeSH
- slezina abnormality MeSH
- svalová únava MeSH
- trombocytopatie MeSH
- vápník metabolismus MeSH
- vápníkové kanály metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aminokyseliny MeSH
- kanály aktivované uvolněním vápníku * MeSH
- membránové proteiny * MeSH
- protein ORAI1 MeSH
- protein STIM1 MeSH
- Stim1 protein, mouse MeSH Prohlížeč
- vápník MeSH
- vápníkové kanály MeSH
The calcium release activated calcium channel is activated by the endoplasmic reticulum-resident calcium sensor protein STIM1. On activation, STIM1 C terminus changes from an inactive, tight to an active, extended conformation. A coiled-coil clamp involving the CC1 and CC3 domains is essential in controlling STIM1 activation, with CC1 as the key entity. The nuclear magnetic resonance-derived solution structure of the CC1 domain represents a three-helix bundle stabilized by interhelical contacts, which are absent in the Stormorken disease-related STIM1 R304W mutant. Two interhelical sites between the CC1α1 and CC1α2 helices are key in controlling STIM1 activation, affecting the balance between tight and extended conformations. Nuclear magnetic resonance-directed mutations within these interhelical interactions restore the physiological, store-dependent activation behavior of the gain-of-function STIM1 R304W mutant. This study reveals the functional impact of interhelical interactions within the CC1 domain for modifying the CC1-CC3 clamp strength to control the activation of STIM1.
- MeSH
- abnormální erytrocyty MeSH
- dyslexie genetika MeSH
- HEK293 buňky MeSH
- ichtyóza genetika MeSH
- kanály aktivované uvolněním vápníku metabolismus MeSH
- klonování DNA MeSH
- konformace nukleové kyseliny MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- metoda terčíkového zámku MeSH
- migréna genetika MeSH
- mióza genetika MeSH
- molekulární modely MeSH
- mutace genetika MeSH
- nádorové proteiny genetika MeSH
- protein ORAI1 genetika MeSH
- protein STIM1 genetika MeSH
- slezina abnormality MeSH
- svalová únava genetika MeSH
- trombocytopatie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kanály aktivované uvolněním vápníku MeSH
- nádorové proteiny MeSH
- ORAI1 protein, human MeSH Prohlížeč
- protein ORAI1 MeSH
- protein STIM1 MeSH
- STIM1 protein, human MeSH Prohlížeč
STIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.
- MeSH
- abnormální erytrocyty metabolismus patologie MeSH
- bakteriální proteiny genetika metabolismus MeSH
- bodová mutace * MeSH
- dyslexie genetika metabolismus patologie MeSH
- exprese genu MeSH
- HEK293 buňky MeSH
- ichtyóza genetika metabolismus patologie MeSH
- interakční proteinové domény a motivy MeSH
- iontový transport MeSH
- konformace proteinů, alfa-helix MeSH
- lidé MeSH
- luminescentní proteiny genetika metabolismus MeSH
- metoda terčíkového zámku MeSH
- migréna genetika metabolismus patologie MeSH
- mióza genetika metabolismus patologie MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- nádorové proteiny chemie genetika metabolismus MeSH
- protein ORAI1 chemie genetika metabolismus MeSH
- protein STIM1 chemie genetika metabolismus MeSH
- regulace genové exprese MeSH
- rekombinantní proteiny chemie genetika metabolismus MeSH
- reportérové geny MeSH
- sekvence aminokyselin MeSH
- slezina abnormality metabolismus patologie MeSH
- substituce aminokyselin MeSH
- svalová únava genetika MeSH
- trombocytopatie genetika metabolismus patologie MeSH
- vápník chemie metabolismus MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zelené fluorescenční proteiny genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- bakteriální proteiny MeSH
- Cyan Fluorescent Protein MeSH Prohlížeč
- luminescentní proteiny MeSH
- nádorové proteiny MeSH
- ORAI1 protein, human MeSH Prohlížeč
- protein ORAI1 MeSH
- protein STIM1 MeSH
- rekombinantní proteiny MeSH
- STIM1 protein, human MeSH Prohlížeč
- vápník MeSH
- yellow fluorescent protein, Bacteria MeSH Prohlížeč
- zelené fluorescenční proteiny MeSH
Torsion of a wandering spleen is rare and has been diagnosed in about 0.2%-0.3% of a large group of patients who required splenectomy. Abnormalities in the ligamentous structures that fix the spleen are thought to be responsible for its abnormal position and for its torsion. Patients may present with various symptoms ranging from mild intermittent abdominal pain to an acute abdomen. Computed tomography leads to correct diagnosis.
- MeSH
- akutní bolest břicha etiologie MeSH
- dospělí MeSH
- infarkt sleziny diagnóza etiologie chirurgie MeSH
- lidé MeSH
- nemoci sleziny komplikace diagnóza chirurgie MeSH
- slezina abnormality MeSH
- torzní deformity diagnóza MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- kazuistiky MeSH
Splenectomy and functional hyposplenism predispose the patient to serious life threatening infections. The most frequent pathogenic organism which causes serious infections in splenectomized adults or hyposplenic patients is Streptococcus pneumoniae. In the etiology of these conditions however also a number of other bacterial and non-bacterial microorganisms may be involved. The risk of serious infections and deaths may be markedly reduced by simple preventive measures, education of the patient, vaccination and antibiotic prophylaxis.
- MeSH
- bakteriální infekce imunologie prevence a kontrola MeSH
- chřipka lidská imunologie prevence a kontrola MeSH
- lidé MeSH
- nemoci sleziny imunologie MeSH
- rizikové faktory MeSH
- slezina abnormality imunologie MeSH
- splenektomie škodlivé účinky MeSH
- vakcinace škodlivé účinky MeSH
- vzdělávání pacientů jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
Torsion of the spleen occurs in children as a rule in combination with ectopy of this organ. It is found in cca one half of the affected children. Abdominal pain is always an associated symptoms. Its intensity depends on other factors such as the degree of torsion, its duration, the pathophysiology of the process etc. The final prognosis can be usually made only during laparotomy. With regard to the relatively rare incidence of this disease, the authors submit the case of a patient operated in their department.
- MeSH
- bolesti břicha etiologie MeSH
- chronická nemoc MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- lidé MeSH
- nemoci sleziny komplikace diagnóza MeSH
- slezina abnormality MeSH
- torzní deformity MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- kazuistiky MeSH
An original observation of the randombred nude rabbit with aplasia of B-lymphoid structures (absence of the follicles in lymph nodes and spleen, no Peyer's plaques). The thymus gland and the T-dependent structures in the spleen and lymph nodes were-on the contrary-well preserved. The nude skin of this genetic rabbit mutant contained large numbers of hair follicles showing almost intrafollicular retention of hairs with their subsequent dysplasia at the subepidermal and ostiopilar level.
- MeSH
- B-lymfocyty patologie MeSH
- králíci abnormality MeSH
- lymfatické uzliny abnormality MeSH
- mutace MeSH
- orgánová specificita MeSH
- Peyerovy pláty abnormality MeSH
- slezina abnormality MeSH
- T-lymfocyty patologie MeSH
- zvířata MeSH
- Check Tag
- králíci abnormality MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The authors describe the case of a patient with an accessory spleen located between the spleen and upper pole of the left kidney. A repeated sonographic examination suggested a suspicion for a kidney tumour, shape anomaly of the spleen, accessory spleen or kidney, but did not exclude even benign tumour in retroperitoneum. Computer tomography proved a formation between the upper pole of the kidney and the spleen, whose density characteristic after a rapid intravenous injection of 60% Verografin at the amount of 1 ml per kg body weight was the same as that of the spleen. Only angiographic examination revealed that the case is an accessory spleen and not a tumour.
The total number of mast cells present in popliteal lymph nodes of hereditarily asplenic Dh/+ mice is lower than in their normal +/+ littermates. The lymph nodes are larger in Dh/+ mice than in normal +/+ littermates. It is postulated that the spleen in some way regulates the number of mast cells in the lymphoid cell population.
- MeSH
- dominantní geny * MeSH
- heterozygot MeSH
- křížení genetické MeSH
- lymfatické uzliny patologie MeSH
- mastocyty cytologie MeSH
- mutantní kmeny myší MeSH
- myši MeSH
- počet buněk MeSH
- slezina abnormality MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
