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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Genes+Dev
2017 ; 31
(6
): 537-552
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BRaf signaling principles unveiled by large-scale human mutation analysis with a
rapid lentivirus-based gene replacement method
#MMPMID28404629
Lim CS
; Kang X
; Mirabella V
; Zhang H
; Bu Q
; Araki Y
; Hoang ET
; Wang S
; Shen Y
; Choi S
; Kaang BK
; Chang Q
; Pang ZP
; Huganir RL
; Zhu JJ
Genes Dev
2017[Mar]; 31
(6
): 537-552
PMID28404629
show ga
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 ?40
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 ?50 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.