{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:18:15Z","timestamp":1790817495604,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,9,18]],"date-time":"2018-09-18T00:00:00Z","timestamp":1537228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"publisher","award":["15K19598"],"award-info":[{"award-number":["15K19598"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"publisher","award":["18K07811"],"award-info":[{"award-number":["18K07811"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Asubio Pharma Co., Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R\/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R\/+ mice compared with Braf+\/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R\/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R\/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK\/ERK signaling, increased body and tail lengths in Braf+\/+ and BrafQ241R\/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1\/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R\/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.<\/jats:p>","DOI":"10.1093\/hmg\/ddy333","type":"journal-article","created":{"date-parts":[[2018,9,17]],"date-time":"2018-09-17T07:14:34Z","timestamp":1537168474000},"page":"74-83","source":"Crossref","is-referenced-by-count":13,"title":["C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome"],"prefix":"10.1093","volume":"28","author":[{"given":"Shin-ichi","family":"Inoue","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Tohoku University School of Medicine, Sendai"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Morozumi","sequence":"additional","affiliation":[{"name":"Immunology and Inflammatory Disease Field, Asubio Pharma Co., Ltd, Kobe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Yoshikiyo","sequence":"additional","affiliation":[{"name":"Immunology and Inflammatory Disease Field, Asubio Pharma Co., Ltd, Kobe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Maeda","sequence":"additional","affiliation":[{"name":"Immunology and Inflammatory Disease Field, Asubio Pharma Co., Ltd, Kobe"},{"name":"End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Tohoku University School of Medicine, Sendai"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,9,18]]},"reference":[{"key":"2019102302292125200_ref1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"Kronenberg","year":"2003","journal-title":"Nature"},{"key":"2019102302292125200_ref2","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/j.ajhg.2012.10.014","article-title":"Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia","volume":"91","author":"Lorget","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2019102302292125200_ref3","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1101\/gad.1179104","article-title":"Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype","volume":"18","author":"Murakami","year":"2004","journal-title":"Genes Dev."},{"key":"2019102302292125200_ref4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/jhg.2015.114","article-title":"Recent advances in RASopathies","volume":"61","author":"Aoki","year":"2016","journal-title":"J. Hum. Genet."},{"key":"2019102302292125200_ref5","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","article-title":"The RASopathies","volume":"14","author":"Rauen","year":"2013","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"2019102302292125200_ref6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1749-6632.2010.05790.x","article-title":"Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms","volume":"1214","author":"Tartaglia","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2019102302292125200_ref7","doi-asserted-by":"crossref","DOI":"10.1210\/er.2017-00232","article-title":"The Rasopathy family: consequences of germline activation of the RAS\/MAPK pathway","author":"Tajan","year":"2018","journal-title":"Endocr. Rev."},{"key":"2019102302292125200_ref8","doi-asserted-by":"crossref","first-page":"R123","DOI":"10.1093\/hmg\/ddw191","article-title":"Pathogenetics of the RASopathies","volume":"25","author":"Tidyman","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2019102302292125200_ref9","doi-asserted-by":"crossref","first-page":"e1149","DOI":"10.1542\/peds.2013-3189","article-title":"Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines","volume":"134","author":"Pierpont","year":"2014","journal-title":"Pediatrics"},{"key":"2019102302292125200_ref10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/ajmg.1320250303","article-title":"New multiple congenital anomalies\/mental retardation syndrome with cardio-facio-cutaneous involvement\u2014the CFC syndrome","volume":"25","author":"Reynolds","year":"1986","journal-title":"Am. J. Med. Genet."},{"key":"2019102302292125200_ref11","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/ng1749","article-title":"Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome","volume":"38","author":"Niihori","year":"2006","journal-title":"Nat. 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Genet."},{"key":"2019102302292125200_ref19","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1073\/pnas.1119803109","article-title":"Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature","volume":"109","author":"De Rocca Serra-Nedelec","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2019102302292125200_ref20","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4274\/Jcrpe.1151","article-title":"Cardio-facio-cutaneous syndrome with precocious puberty, growth hormone deficiency and hyperprolactinemia","volume":"6","author":"Celik","year":"2014","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"2019102302292125200_ref21","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1002\/ajmg.a.37260","article-title":"Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: patterns of growth, puberty and final height data","volume":"167A","author":"Tamburrino","year":"2015","journal-title":"Am. J. Med. Genet. A."},{"key":"2019102302292125200_ref22","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1093\/hmg\/ddt162","article-title":"The ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation","volume":"22","author":"Ono","year":"2013","journal-title":"Hum. Mol. 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