A new syndrome: thrombocytopathia, muscle fatigue, asplenia, miosis, migraine, dyslexia and ichthyosis

Stormorken, Helge; Sjaastad, Ottar; Langslet, A; Sulg, I; Egge, K.; Diderichsen, Jørgen

doi:10.1111/j.1399-0004.1985.tb02209.x

Cited by 67 publications

(58 citation statements)

References 7 publications

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“…One of the two YPS mutations, c.910C>T, is the same STIM1 mutation reported in patients with Stormorken syndrome, a tubular aggregate myopathy with thrombocytopenia, miosis and functional or anatomical asplenia (12), (28, 29). The second YPS mutation, c.343A>T was previously reported as a de novo mutation in a female child with apparently isolated tubular aggregate myopathy who, similar to our patients, presented at age 4 years with limb girdle weakness with a positive Gower's sign (10).…”

Section: Discussionmentioning

confidence: 73%

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

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: 73%

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

127

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“…a constellation of symptoms, including congenital miosis, bleeding diathesis, thrombocytopenia, functional (or anatomical) asplenia, and proximal muscle weakness (29). Other manifestations include ichthyosis, headaches, and dyslexia (30).…”

mentioning

confidence: 99%

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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“…Holth & Berner's case (1921), or it may be combined with various other neurological symptoms and signs, such as spastic ataxia (of the Sanger Brown type) and nystagmus (Dick et al 1983). In the present context, congenital miosis is an integral feature of a syndrome with a wide spectrum of symptoms and signs (Stormorken et al 1985). Holth & Berner (1921) demonstrated, probably as the first ones, an aplasia of the dilatator pupillae muscle in oligo-symptomatic congenital miosis (biopsy as well as autopsy study).…”

Section: Discussionmentioning

confidence: 97%

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

Sjaastad

Aasly

Stormorken

et al. 1992

Acta Ophthalmologica

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A recently described familiar syndrome consists of the following components: A bleeding tendency with thrombocytopathia, miosis, muscular weakness and spasms, ichthyosis, asplenia, dyslexia, and headache. Four definite and 2 probable patients have been identified in 4 generations. In the present study, the pupillary behaviour was scrutinized in two 'definite' cases with the infrared, binocular pupillometer. The forehead sweating pattern was also investigated with an Evaporimeter. The basal pupillary widths were: 1.25-1.75 mm. Only minor responses were noted upon topical stimulation with an indirectly acting pupillodilating agent (OH-amphetamine). A directly acting sympathicomimetic drug (phenylephrine) exerted a more marked influence on the pupil, indicating a relative supersensitivity. The evaporimetric pattern in the forehead seemed to be within reference limits, at variance with what is the case in Horner's syndrome. Further findings were: the orbit seemed to be smaller than normal; a bilateral VI. cranial nerve palsy was identified, and a marked upward gaze palsy coexisted with pupils with Argyll Robertson's traits. There is no readily acceptable explanation for the ocular abnormalities. The disorder underlying the pupillary abnormality may possibly be located in the upper mesencephalon.

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A new syndrome: thrombocytopathia, muscle fatigue, asplenia, miosis, migraine, dyslexia and ichthyosis

Cited by 67 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

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

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

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