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1.
Neuropathology ; 40(6): 559-569, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33073872

RESUMEN

Tubular aggregate myopathy (TAM) is a progressive disorder characterized by muscle weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome (STRMK), combining TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. TAM and STRMK arise from gain-of-function mutations in STIM1 (stromal interaction molecule 1) or ORAI1, both encoding key regulators of Ca2+ homeostasis, and mutations in either gene result in excessive extracellular Ca2+ entry. The pathomechanistic similarities and differences between TAM and STRMK are only partially understood. Here we provide functional in vitro experiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants recruit ORAI1 to the clusters, increase cytosolic Ca2+ levels, promote major nuclear import of the Ca2+ -dependent transcription factor NFAT (nuclear factor of activated T cells), and trigger the formation of circular membrane stacks. In conclusion, the analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function and downstream effects of excessive Ca2+ entry, highlighting that TAM and STRMK involve a common pathomechanism.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Dislexia/genética , Ictiosis/genética , Trastornos Migrañosos/genética , Miosis/genética , Miopatías Estructurales Congénitas/genética , Proteínas de Neoplasias/genética , Bazo/anomalías , Molécula de Interacción Estromal 1/genética , Animales , Trastornos de las Plaquetas Sanguíneas/metabolismo , Trastornos de las Plaquetas Sanguíneas/patología , Células Cultivadas , Dislexia/metabolismo , Dislexia/patología , Eritrocitos Anormales/metabolismo , Eritrocitos Anormales/patología , Humanos , Ictiosis/metabolismo , Ictiosis/patología , Ratones , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/patología , Miosis/metabolismo , Miosis/patología , Fatiga Muscular/genética , Mutación , Miopatías Estructurales Congénitas/metabolismo , Miopatías Estructurales Congénitas/patología , Factores de Transcripción NFATC/metabolismo , Proteína ORAI1/metabolismo , Bazo/metabolismo , Bazo/patología , Transfección
2.
Sci Rep ; 9(1): 14568, 2019 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-31601825

RESUMEN

Translation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of the phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by relying on cells differentiated from human pluripotent stem cells. To analyse the benefits provided by this approach, we chose to focus on Friedreich ataxia, a neurodegenerative condition for which the recent clinical testing of two compounds was not successful. These compounds, namely, resveratrol and nicotinamide, were selected because they had been shown to stimulate the expression of frataxin in fibroblasts and lymphoblastoid cells. Our results indicated that these compounds failed to do so in iPSC-derived neurons generated from two patients with Friedreich ataxia. By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.


Asunto(s)
Ataxia de Friedreich/genética , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Proteínas de Unión a Hierro/genética , Neuronas/efectos de los fármacos , Niacinamida/farmacología , Resveratrol/farmacología , Apoptosis , Supervivencia Celular , Células Cultivadas , Diseño de Fármacos , Fibroblastos/citología , Ataxia de Friedreich/tratamiento farmacológico , Perfilación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , Cariotipificación , Neuronas/citología , Fenotipo , Investigación Biomédica Traslacional , Frataxina
3.
Neuromuscul Disord ; 27(1): 78-82, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27876257

RESUMEN

STIM1 is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Missense mutations in the luminal domain have been associated with tubular aggregate myopathy (TAM), while cytosolic mutations can cause Stormorken syndrome, a multisystemic disease associating TAM with asplenia, thrombocytopenia, miosis, ichthyosis, short stature and dyslexia. Here we present the case of a 41-year-old female complaining of exercise intolerance. Clinical examination showed short stature, scoliosis, proximal muscle weakness with lower limb predominance, and ophthalmoplegia. Laboratory tests revealed hypocalcemia, mild anemia and elevated creatine kinase (CK) levels. Whole-body muscle magnetic resonance imaging (MRI) revealed asplenia. Muscle biopsy was consistent with TAM. STIM1 gene analysis disclosed the novel c.252T>A, p.D84E missense mutation which was shown to induce constitutive STIM1 clustering in a functional study. This study reports a novel STIM1 mutation located in the Ca2+-binding EF domain causing TAM with features of Stormorken syndrome.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Dislexia/genética , Ictiosis/genética , Trastornos Migrañosos/genética , Miosis/genética , Miopatías Estructurales Congénitas/genética , Proteínas de Neoplasias/genética , Bazo/anomalías , Molécula de Interacción Estromal 1/genética , Adulto , Eritrocitos Anormales , Femenino , Humanos , Fatiga Muscular/genética , Mutación Missense
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