Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Morin, Gilles; Bruechle, Nadina Ortiz; Singh, Amrathlal Rabbind; Knopp, Cordula; Jedraszak, Guillaume; Elbracht, Miriam; Brémond‐Gignac, Dominique; Hartmann, Kathi; Sevestre, Henri; Deutz, Peter; Herent, Didier; Nürnberg, Peter; Roméo, Bruno; Konrad, Kerstin; Mathieu‐Dramard, Michèle; Oldenburg, J.; Bourges-Petit, Elisabeth; Shen, Yuequan; Zerres, Klaus; Ouadid-Ahidouch, Halima; Rochette, Jacques

doi:10.1002/humu.22722

Cited by 11 publications

(49 citation statements)

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“…The molecular mechanisms controlling this transition are incompletely understood but were proposed to involve hydrophobic (10) and electrostatic interactions (9,21,26) between the CC1 and CC2 domains of STIM1-CT. The role of CC1 in maintaining STIM1-CT in a closed, inactive conformation has been demonstrated by in vitro studies (10,11) and is emphasized by recent reports identifying a gain-of-function mutation in CC1 (R304W) as the cause of Stormorken syndrome (27)(28)(29). Our studies of the R429C patient mutation highlight a hitherto unappreciated role for CC3 in addition to CC1 in maintaining the inactive conformation of STIM1, as mutant STIM1-R429C adopts a constitutively open conformation and localizes to ER-PM junctions independently of ER store Ca 2+ content.…”

Section: Discussionmentioning

confidence: 99%

Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Maus

Jairaman

Stathopulos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Store-operated Ca 2+ entry (SOCE) is a universal Ca 2+ influx pathway that is important for the function of many cell types. SOCE occurs upon depletion of endoplasmic reticulum (ER) Ca 2+ stores and relies on a complex molecular interplay between the plasma membrane (PM) Ca 2+ channel ORAI1 and the ER Ca 2+ sensor stromal interaction molecule (STIM) 1. Patients with null mutations in ORAI1 or STIM1 genes present with severe combined immunodeficiency (SCID)-like disease. Here, we describe the molecular mechanisms by which a loss-of-function STIM1 mutation (R429C) in human patients abolishes SOCE. R429 is located in the third coiled-coil (CC3) domain of the cytoplasmic C terminus of STIM1. Mutation of R429 destabilizes the CC3 structure and alters the conformation of the STIM1 C terminus, thereby releasing a polybasic domain that promotes STIM1 recruitment to ER-PM junctions. However, the mutation also impairs cytoplasmic STIM1 oligomerization and abolishes STIM1-ORAI1 interactions. Thus, despite its constitutive localization at ER-PM junctions, mutant STIM1 fails to activate SOCE. Our results demonstrate multifunctional roles of the CC3 domain in regulating intra-and intermolecular STIM1 interactions that control (i) transition of STIM1 from a quiescent to an active conformational state, (ii) cytoplasmic STIM1 oligomerization, and (iii) STIM1-ORAI1 binding required for ORAI1 activation.release-activated Ca 2+ (CRAC) channels in the plasma membrane (PM) that are formed by multimers of ORAI proteins, which constitute the permeation pore of the channel (1-4). The opening of ORAI channels is mediated by stromal interaction molecule (STIM) 1 and STIM2, single pass transmembrane proteins whose N and C termini are located in the endoplasmic reticulum (ER) lumen and cytoplasm, respectively (5, 6). STIM1 and STIM2 are activated after depletion of ER Ca 2+ stores in response to ligation of cell surface receptors that mediate phospholipase C (PLC) activation. The importance of SOCE is emphasized by null and loss-of-function mutations in ORAI1 and STIM1 genes, which cause a disease syndrome called CRAC channelopathy that is characterized by immunodeficiency, autoimmunity, ectodermal dysplasia, and skeletal myopathy (7). SOCE is a highly choreographed process that involves a complex conformational rearrangement of STIM1 proteins, their oligomerization in the ER lumen and in the cytoplasm, and subsequent translocation from the bulk ER to ER-PM junctions (4, 8). There, STIM1 oligomers form puncta and bind ORAI1. SOCE is initiated by dissociation of Ca 2+ from a paired EF-hand (EFh) domain in the ER luminal N terminus of STIM1 after store depletion (Fig. 1A) and association of STIM1 N termini. These events result in a conformational extension of the cytoplasmic

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Section: Discussionmentioning

confidence: 99%

Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Maus

Jairaman

Stathopulos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…While heterozygous gain‐of‐function mutations in STIM1 or ORAI1 generate excessive Ca 2+ influx and result in the development of TAM/Stormorken syndrome [Bohm et al., ; Bohm et al., ; Hedberg et al., ; Misceo et al., ; Morin et al., ; Nesin et al., ; Endo et al., ; Markello et al., ], homozygous loss‐of‐function mutations in either of the genes suppress Ca 2+ influx and are associated with severe immunodeficiency [Feske et al., ; McCarl et al., ; Picard et al., ; Byun et al., ; Fuchs et al., ; Lacruz and Feske ] (MIM# 612782, # 612783). We conclude that strict regulation of Ca 2+ homeostasis ensures normal physiology of muscle, leucocytes, platelets, skin, and other cells and tissues, and that overactive SOCE causes TAM/Stormorken syndrome, whereas underactive SOCE causes immunodeficiency.…”

Section: Discussionmentioning

confidence: 99%

ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy

et al. 2017

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Calcium (Ca2+) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store‐operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain‐of‐function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss‐of‐function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation‐dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non‐muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.

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“…Both syndromes can be caused by the same GoF mutation in STIM1; in addition, another GoF mutation in STIM1 causes either York platelet syndrome or TAM (Figs. and ; Table ) . All three diseases therefore appear to be part of the same clinical spectrum, with the phenotype and expressivity resulting from the mutation being determined by additional factors such as allelic variation or modifier genes.…”

Section: Gof Mutations In Orai1 and Stim1mentioning

confidence: 97%

Diseases caused by mutations in ORAI1 and STIM1

Lacruz

Feske

2015

Annals of the New York Academy of Sciences

393

406

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Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific form of Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are formed by ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in dental enamel. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in these genes result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including non-syndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes, two syndromes defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology.

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Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Cited by 11 publications

References 0 publications

Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy

Diseases caused by mutations in ORAI1 and STIM1

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