RESUMEN
Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.
Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Dislexia/genética , Ictiosis/genética , Proteínas de la Membrana/genética , Trastornos Migrañosos/genética , Miosis/genética , Proteínas de Neoplasias/genética , Mutación Puntual , Bazo/anomalías , Adolescente , Adulto , Anciano , Trastornos de las Plaquetas Sanguíneas/metabolismo , Trastornos de las Plaquetas Sanguíneas/patología , Calcio/metabolismo , Canales de Calcio/metabolismo , Niño , Preescolar , Dislexia/metabolismo , Dislexia/patología , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/ultraestructura , Eritrocitos Anormales/metabolismo , Eritrocitos Anormales/patología , Femenino , Humanos , Ictiosis/metabolismo , Ictiosis/patología , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/patología , Miosis/metabolismo , Miosis/patología , Fatiga Muscular/genética , Fibras Musculares Esqueléticas/patología , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Linaje , Estructura Secundaria de Proteína , Bazo/metabolismo , Bazo/patología , Molécula de Interacción Estromal 1RESUMEN
OBJECTIVE: To evaluate the efficacy and tolerability of subcutaneous (SC) treprostinil, a prostacyclin analogue, in young children with refractory pulmonary arterial hypertension. STUDY DESIGN: Eight children (median age, 4 years) received SC treprostinil therapy after failure of combined oral treatment (n = 7) or because of severe complications with intravenous epoprostenol (n = 1). Treprostinil was delivered through an SC catheter at gradually increasing doses to an average of 40 ng/kg/min, depending on the presence of adverse effects. RESULTS: Seven patients demonstrated early significant improvement (in functional class, hemodynamics, and/or 6-minute walk distance; P <.05), and 6 had a sustained good response. Site pain could be effectively managed in all but one child. CONCLUSIONS: Treprostinil may be a potentially valuable rescue therapy in children with refractory pulmonary arterial hypertension, but further study in a larger number of patients is needed.