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1.
Nat Commun ; 8(1): 1052, 2017 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-29051493

RESUMEN

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.


Asunto(s)
Encéfalo/anatomía & histología , Discapacidad Intelectual/genética , Megalencefalia/genética , Mutación , Proteína Homóloga de Ras Enriquecida en el Cerebro/genética , Serina-Treonina Quinasas TOR/metabolismo , Animales , Movimiento Celular , Tamaño de la Célula , Células Cultivadas , Humanos , Discapacidad Intelectual/patología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Tamaño de los Órganos , Convulsiones/genética , Transducción de Señal/genética , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Pez Cebra/genética
2.
Clin Genet ; 88(3): 224-33, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25131214

RESUMEN

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.


Asunto(s)
Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Mutación , Fenotipo , Eliminación de Secuencia , Adolescente , Adulto , Niño , Preescolar , Exones , Facies , Femenino , Humanos , Lactante , Masculino , Adulto Joven
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