RESUMEN
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.
Asunto(s)
Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/genética , Neuronas/metabolismo , Sinapsis/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/genética , Adolescente , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Epilepsia/metabolismo , Exocitosis , Femenino , Heterocigoto , Humanos , Lípidos/química , Imagen por Resonancia Magnética , Masculino , Fusión de Membrana , Trastornos del Movimiento/genética , Mutación , Trastornos del Neurodesarrollo/metabolismo , Neurotransmisores/metabolismo , Fenotipo , Dominios Proteicos , Proteínas R-SNARE/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/fisiologíaRESUMEN
INTRODUCTION: Gum Arabic (GA) is a complex polysaccharide with proven prebiotic properties and potentially beneficial systemic effects. METHODS: We randomly allocated 36 chronic kidney disease (CKD) patients to receive 10, 20, or 40 grams daily of GA for four weeks and studied the systemic effects of this intervention. RESULTS: Thirty participants completed the study with baseline glomerular filtration rate 29.1 ± 9.9 mL/min/1.7 m2. In contrast to previous observations, we found no effect on serum urea or creatinine levels. GA supplementation was associated with a small but statistically significant drop in serum sodium level (138 ± 2 to 136 ± 3 mmol/L, p = 0.002) without affecting other electrolytes, urine volume, or indoxyl sulfate (IS) levels. GA supplementation was also associated with a significant drop in C-reactive protein (CRP) level (3.5 ± 1.5 to 2.8 ± 1.6 ng/mL, p = 0.02) even in patients who received only 10 g/day (4.4 ± 1.2 to 3.2 ± 1.5 ng/mL, p = 0.03). CONCLUSIONS: Supplementing the diet of CKD patients with 10-40 g/day of GA significantly reduced CRP level which could have a positive impact on these patients' morbidity and mortality. This trial is registered with Saudi Clinical Trial Registry number 15011402.