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10.1093/hmg/ddu376 http://scihub22266oqcxt.onion/10.1093/hmg/ddu376 25035421!ä!25035421 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 298.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Hum+Mol+Genet 2014 ; 23 (24): 6553-66 Nephropedia Template TP {{tp|p=25035421|t=2014. New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome |pdf=|usr=}}{{25035421}} gab.com Text New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome JO: Hum Mol Genet http://www.kidney.de/pget.php?&tw=1&pmid=25035421 #FOAvip Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knockin mice (here Braf(Q241R/+)) expressing the Braf Q241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf(Q241R/+) mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf(Q241R/+) embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knockin mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf(Q241R/+) embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new Braf knockin mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome. Twit Text FOAVip New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome ????Hum Mol Genet http://www.kidney.de/pget.php?&tw=1&pmid=25035421 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25035421 #FOAvip English Wikipedia <ref>{{Cite pmid|25035421}}</ref> New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome #MMPMID25035421 Inoue S; Moriya M; Watanabe Y; Miyagawa-Tomita S; Niihori T; Oba D; Ono M; Kure S; Ogura T; Matsubara Y; Aoki Y Hum Mol Genet 2014[Dec]; 23 (24): 6553-66 PMID25035421show ga Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knockin mice (here Braf(Q241R/+)) expressing the Braf Q241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf(Q241R/+) mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf(Q241R/+) embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knockin mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf(Q241R/+) embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new Braf knockin mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome. |Animals[MESH] |Benzamides/*pharmacology[MESH] |Benzazepines/*pharmacology[MESH] |Diphenylamine/*analogs & derivatives/pharmacology[MESH] |Disease Models, Animal[MESH] |Drug Synergism[MESH] |Ectodermal Dysplasia/*drug therapy/*genetics/metabolism/pathology[MESH] |Embryo, Mammalian[MESH] |Facies[MESH] |Failure to Thrive/*drug therapy/*genetics/metabolism/pathology[MESH] |Female[MESH] |Gene Expression Regulation[MESH] |Gene Knock-In Techniques[MESH] |Genes, Lethal[MESH] |Heart Defects, Congenital/*drug therapy/*genetics/metabolism/pathology[MESH] |Histone Deacetylase Inhibitors/pharmacology[MESH] |Histone Demethylases/antagonists & inhibitors/genetics/metabolism[MESH] |Humans[MESH] |Liver/abnormalities/drug effects[MESH] |MAP Kinase Kinase Kinases/antagonists & inhibitors/genetics/metabolism[MESH] |Male[MESH] |Mice[MESH] |Mice, Transgenic[MESH] |Mutation[MESH] |Myocardium/pathology[MESH] |Protein Kinase Inhibitors/pharmacology[MESH] |Proto-Oncogene Proteins B-raf/*genetics/metabolism[MESH] |Pyrimidines/*pharmacology[MESH] |Signal Transduction[MESH]New BRAF knockin mice provide a pathogenetic mechanism of developmenta(epmc).pdf DeepDyve Pubget Overpricing