Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Byun, Minji; Abhyankar, Avinash; Lelarge, Virginie; Plancoulaine, Sabine; Palandüz, Ayşe; Telhan, Leyla; Boisson, Bertrand; Pïcard, Capucine; Dewell, Scott; Zhao, Connie; Jouanguy, Emmanuelle; Feske, Stefan; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1084/jem.20101597

Cited by 262 publications

(230 citation statements)

References 35 publications

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“…These mutations illustrate the phenotypic effects of hyperactive CRAC channel signaling and contrast the immune deficiency syndrome observed in biallelic loss-of-function mutations in these genes (21)(22)(23). Our data are supported by independent studies in mice, in which an activating mutation in the EF hand of STIM1 (p.D84G) led to premature platelet activation and bleeding, one of the symptoms in patients with Stormorken syndrome (44).…”

Section: Discussionsupporting

confidence: 78%

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Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

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

216

345

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Signaling through the store-operated Ca 2+ release-activated Ca 2+ (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca 2+ homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca 2+ sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca 2+ -dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca 2+ entry in the treatment of patients with Stormorken syndrome and related pathologic conditions. human genetics | calcium signaling C a 2+ influx in response to the depletion of intracellular Ca 2+ stores, or store-operated Ca 2+ entry, constitutes one of the major routes of Ca 2+ entry in all animal cells (1). Under physiological conditions, Ca 2+ influx is activated in response to numerous G protein-coupled receptors and receptor tyrosine kinases signaling via inositol-1,4,5-trisphosphate as a second messenger (2). Store-operated Ca 2+ entry is mediated primarily by the Ca 2+ release-activated Ca 2+ (CRAC) channel (3), which consists of the pore-forming subunits ORAI1-3 (or CRAC modulators 1-3) and Ca 2+ sensors, STIM1 and STIM2 (4-7). STIM proteins reside in the membrane of endoplasmic reticulum (ER), whereas ORAI proteins reside in the plasma membrane. STIM1 is a single transmembrane-spanning protein (8-12) that, in resting cells, exists as a dimer that binds Ca 2+ through two EF hand-containing domains located in the ER lumen (13). Depletion of Ca 2+ in the ER induces a series of molecular events in the conformation and localization of STIM1, initiated by the formation of higher-order oligomers, protein unfolding, and accumulation at discrete sites in the cell where the ER membrane is in close proximity to the plasma membrane (11,(13)(14)(15)(16). In these sites, STIM1 binds to the cytosolic C and N termini of ORAI1 (17, 18), resulting in channel activation and generation of a highly Ca 2+ -selective CRAC current, or I CRAC (3,19,20). I CRAC is responsible not only ...

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Section: Discussionsupporting

confidence: 78%

“…Consistent with a fundamental role of the CRAC channel in cell signaling, loss-of-function mutations in STIM1 or ORAI1 lead to immune deficiency and nonprogressive myopathy (21)(22)(23). However, evidence that gain-of-function mutations in STIM1 and ORAI1 can affect human health is only recently starting to emerge.…”

mentioning

confidence: 96%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

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

216

345

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“…Ng et al 71 Hoischen et al 33 Ng et al 30 Simpson et al 72 Isidor et al 73 Vissers et al 74 Albers et al 75 Dickinson et al 76 Sirmaci et al 77 Agrawal et al 78 De novo (Figure 3e Byun et al 79 Haack et al 80 Worthey et al 44 Götz et al 69c Erlich et al 45 Ozgul et al 81 a,b,c Indicate studies that use a combination of two strategies.…”

Section: Affecting Protein Sequencementioning

confidence: 99%

Disease gene identification strategies for exome sequencing

et al. 2012

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“…We discovered the first (to our knowledge) primary immunodeficiencies underlying Kaposi sarcoma in children with other infectious and tumoral phenotypes. We then determined the genetic basis of rare cases of isolated, classic KS in childhood: mutations of the stromal interaction molecule 1 (STIM1) and OX40 genes (107,108). These studies, which we are currently pursuing, served as a platform for a much more difficult and innovative study, that of herpes simplex virus encephalitis (HSE).…”

Section: Miscellaneous Endeavorsmentioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

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

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201

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Abstract: Whole-exome sequencing reveals a homozygous splice-site mutation in the gene encoding STIM1 in a child with classic Kaposi sarcoma.

Cited by 262 publications

References 35 publications

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Disease gene identification strategies for exome sequencing

Severe infectious diseases of childhood as monogenic inborn errors of immunity

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