A new hereditary syndrome with a bleeding tendency, extreme miosis, spasms, dyslexia, thrombocytopathia etc.

Sjaastad, Ottar; Aasly, Jan; Stormorken, Helge; Wysocka-Bakowska, MM; Hørven, Ivar; Fredriksen, Torbjørn A

doi:10.1111/j.1755-3768.1992.tb04874.x

Cited by 5 publications

(7 citation statements)

References 7 publications

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“…Both Stormorken syndrome (31), and YPS are associated with myopathy. Stormorken patients have miosis (32), and two of our patients (A-II-2 and A-III-1) have small, fixed pupils that did not accommodate to darkness or respond to light or medications. Atrophy of the extraocular muscles on imaging and the clinical observation of restricted vertical and horizontal eye movements suggest a myopathy of the oculomotor muscles.…”

Section: Discussionmentioning

confidence: 72%

York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1

Markello

Chen

Kwan

et al. 2015

Molecular Genetics and Metabolism

101

127

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Store-operated Ca2+ entry is the major route of replenishment of intracellular Ca2+ in animal cells in response to depletion of Ca2+ stores in the endoplasmic reticulum. It is primarily mediated by the Ca2+ selective release-activated Ca2+ (CRAC) channel which consists of the pore-forming subunits ORAI1–3 and the Ca2+ sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca2+ as a result of store-operated Ca2+ entry is essential for platelet activation. York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron opaque organelles and massive, multi-layered target bodies and deficiency of platelet Ca2+ storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS.

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Section: Discussionmentioning

confidence: 72%

York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1

Markello

Chen

Kwan

et al. 2015

Molecular Genetics and Metabolism

101

127

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“…Analysis performed on three of our patients (F1 II-2, F1 III-1, and F2 II-3) displayed normal B, T, and NK cell numbers, normal levels of immunoglobulins, normal responses to T cell mitogens, and antibody responses to tetanus and diphtheria vaccine. In contrast to ORAI1-and STIM1-deficient patients who have enlarged spleens, our patients have asplenia/hyposplenia [Stormorken et al, 1985;Sjaastad et al, 1992;Mizobuchi et al, 2000;Stormorken, 2002]. The spleen plays important roles in host defense such as B cell maturation and phagocytosis of microbes, and congenital asplenia is a severe health condition [Leahy et al, 2005;Koss et al, 2012].…”

Section: Discussionmentioning

confidence: 83%

“…The patients belong to four families (Fig. 1C): the original two patients described by Stormorken et al (1985Stormorken et al ( , 1995 (family 1) [Sjaastad et al, 1992;Stormorken et al, 1985Stormorken et al, , 1995, a Norwegian male (family 2), a French male (family 3), and a mother and daughter from Japan (family 4) [Mizobuchi et al, 2000].…”

Section: Detection Of the Disease-causing Mutation In Stormorken Syndmentioning

confidence: 99%

A Dominant STIM1 Mutation Causes Stormorken Syndrome

et al. 2014

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Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.

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“…Clinical phenotype. Detailed reviews and clinical descriptions of Stormorken syndrome 96,135,146,147 and York platelet syndrome [136][137][138][139] have been published elsewhere. We here discuss the clinical phenotypes in the context of a newly reported STIM1 mutation and data from animal models.…”

Section: Stormorken Syndrome and York Platelet Syndromementioning

confidence: 99%

Diseases caused by mutations in ORAI1 and STIM1

Lacruz

Feske

2015

Annals of the New York Academy of Sciences

402

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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A new hereditary syndrome with a bleeding tendency, extreme miosis, spasms, dyslexia, thrombocytopathia etc.

Cited by 5 publications

References 7 publications

York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1

York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1

A Dominant STIM1 Mutation Causes Stormorken Syndrome

Diseases caused by mutations in ORAI1 and STIM1

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