BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method.
Genes Dev
; 31(6): 537-552, 2017 03 15.
Article
en En
| MEDLINE
| ID: mdl-28404629
ABSTRACT
Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene-mutation-cell-behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and â¼40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and â¼50 disease-linked BRaf mutants, including all CFC-linked mutants. Analysis of simultaneous multiple patch-clamp recordings from 6068 pairs of rat neurons with validation in additional mouse and human neurons and multiple learning tests from 1486 rats identified BRaf as the key missing signaling effector in the common synaptic NMDA-R-CaMKII-SynGap-Ras-BRaf-MEK-ERK transduction cascade. Moreover, the analysis creates the original big data unveiling three general features of BRaf signaling. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Transmisión Sináptica
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Sistema de Señalización de MAP Quinasas
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Proteínas Proto-Oncogénicas B-raf
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Mutación
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Genes Dev
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos