RESUMEN
NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Discapacidades para el Aprendizaje/genética , Mutación , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Adolescente , Animales , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Niño , Femenino , Expresión Génica , Genotipo , Células HEK293 , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Discapacidades para el Aprendizaje/diagnóstico , Discapacidades para el Aprendizaje/patología , Masculino , Ratones , Ratones Noqueados , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Linaje , Fenotipo , Embarazo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transcriptoma , Adulto JovenRESUMEN
The transient receptor potential (TRP) channels family are cationic channels involved in various physiological processes as pain, inflammation, metabolism, swallowing function, gut motility, thermoregulation or adipogenesis. In the oral cavity, TRP channels are involved in chemesthesis, the sensory chemical transduction of spicy ingredients. Among them, TRPA1 is activated by natural molecules producing pungent, tingling or irritating sensations during their consumption. TRPA1 can be activated by different chemicals found in plants or spices such as the electrophiles isothiocyanates, thiosulfinates or unsaturated aldehydes. TRPA1 has been as well associated to various physiological mechanisms like gut motility, inflammation or pain. Cinnamaldehyde, its well known potent agonist from cinnamon, is reported to impact metabolism and exert anti-obesity and anti-hyperglycemic effects. Recently, a structurally similar molecule to cinnamaldehyde, cuminaldehyde was shown to possess anti-obesity and anti-hyperglycemic effect as well. We hypothesized that both cinnamaldehyde and cuminaldehyde might exert this metabolic effects through TRPA1 activation and evaluated the impact of cuminaldehyde on TRPA1. The results presented here show that cuminaldehyde activates TRPA1 as well. Additionally, a new natural agonist of TRPA1, tiglic aldehyde, was identified and p-anisaldehyde confirmed.
Asunto(s)
Acroleína/análogos & derivados , Benzaldehídos/farmacología , Cimenos/farmacología , Canal Catiónico TRPA1/agonistas , Acroleína/farmacología , Aldehídos/farmacología , Animales , Células CHO , Cricetulus , Ganglios Espinales/citología , Neuronas , Análisis de la Célula Individual , Canal Catiónico TRPA1/genética , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , TransfecciónRESUMEN
Various lines of published evidence have already demonstrated the impact of TRPV1 agonists on energetic metabolism through the stimulation of the sympathetic nervous system (SNS). This study presents a trial investigating if stimulation of the two related sensory receptors TRPA1 and TRPM8 could also stimulate the SNS and impact the energetic metabolism of healthy subjects. The trial was designed to be double-blinded, randomized, cross-over, placebo-controlled with healthy subjects and the impact on the energetic metabolism and the autonomic nervous system (ANS) of cinnamaldehyde, capsaicin and a cooling flavor was measured during the 90 min after ingestion. Energy expenditure and substrate oxidation were measured by indirect calorimetry. An exploratory method to measure ANS activity was by facial thermography and power spectral analysis of heart rate variability using ECG was also used. Following cinnamaldehyde ingestion, energy expenditure was increased as compared to placebo. Furthermore, postprandial fat oxidation was maintained higher compared to placebo after cinnamaldehyde and capsaicin ingestion. Similar peripheral thermoregulation was observed after capsaicin and cinnamaldehyde ingestion. Unlike capsaicin, the dose of cinnamaldehyde was not judged to be sensorially 'too intense' by participants suggesting that Cinnamaldehyde would be a more tolerable solution to improve thermogenesis via spicy ingredients as compared to capsaicin.