RESUMEN
Cell-adhesion molecules play critical roles in brain development, as well as maintaining synaptic structure, function, and plasticity. Here we have found the disruption of two genes encoding putative cell-adhesion molecules, CDH15 (cadherin superfamily) and KIRREL3 (immunoglobulin superfamily), by a chromosomal translocation t(11;16) in a female patient with intellectual disability (ID). We screened coding regions of these two genes in a cohort of patients with ID and controls and identified four nonsynonymous CDH15 variants and three nonsynonymous KIRREL3 variants that appear rare and unique to ID. These variations altered highly conserved residues and were absent in more than 600 unrelated patients with ID and 800 control individuals. Furthermore, in vivo expression studies showed that three of the CDH15 variations adversely altered its ability to mediate cell-cell adhesion. We also show that in neuronal cells, human KIRREL3 colocalizes and interacts with the synaptic scaffolding protein, CASK, recently implicated in X-linked brain malformation and ID. Taken together, our data suggest that alterations in CDH15 and KIRREL3, either alone or in combination with other factors, could play a role in phenotypic expression of ID in some patients.
Asunto(s)
Cadherinas/genética , Proteínas Portadoras/genética , Moléculas de Adhesión Celular Neuronal/genética , Variación Genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Cadherinas/química , Cadherinas/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Estudios de Casos y Controles , Adhesión Celular , Moléculas de Adhesión Celular Neuronal/química , Moléculas de Adhesión Celular Neuronal/metabolismo , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 16 , Estudios de Cohortes , Femenino , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Estructura Terciaria de Proteína , Translocación GenéticaRESUMEN
Two angiotensin II (Ang II)-specific receptors, AGTR1 and AGTR2, are expressed in the mammalian brain. Ang II actions on blood pressure regulation, water electrolyte balance, and hormone secretion are primarily mediated by AGTR1. The function of AGTR2 remains unclear. Here, we show that expression of the AGTR2 gene was absent in a female patient with mental retardation (MR) who had a balanced X;7 chromosomal translocation. Additionally, 8 of 590 unrelated male patients with MR were found to have sequence changes in the AGTR2 gene, including one frameshift and three missense mutations. These findings indicate a role for AGTR2 in brain development and cognitive function.