{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:14:50Z","timestamp":1792811690248,"version":"4.5.0"},"reference-count":78,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"vor","delay-in-days":184,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The American Journal of Human Genetics"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1016\/j.ajhg.2021.09.007","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T12:32:51Z","timestamp":1633696371000},"page":"2112-2129","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":78,"title":["SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype"],"prefix":"10.1016","volume":"108","author":[{"given":"Marialetizia","family":"Motta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Fasano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Gredy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Brinkmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline Alice","family":"Bonnard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pelin Ozlem","family":"Simsek-Kiper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif Yilmaz","family":"Gulec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Essaddam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulen Eda","family":"Utine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Guarnetti Prandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Venditti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pantaleoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ciolfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Petrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Consoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Vignal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Hepbasli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Ullrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisenka E.L.M.","family":"Vissers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Gritli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"De Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saayda","family":"Ben Becher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Gelb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Dallapiccola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Lauri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Chillemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Schuh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Cav\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Zenker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ajhg.2021.09.007_bib1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/02699050500284218","article-title":"The extracellular signal-regulated\u00a0kinase: multiple substrates regulate diverse cellular functions","volume":"24","author":"Yoon","year":"2006","journal-title":"Growth Factors"},{"key":"10.1016\/j.ajhg.2021.09.007_bib2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1177\/1947601911408081","article-title":"Functional specificity of\u00a0ras isoforms: so similar but so different","volume":"2","author":"Castellano","year":"2011","journal-title":"Genes Cancer"},{"key":"10.1016\/j.ajhg.2021.09.007_bib3","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1101\/gad.11.19.2468","article-title":"K-ras is an essential gene in the mouse with partial functional overlap with N-ras","volume":"11","author":"Johnson","year":"1997","journal-title":"Genes Dev."},{"key":"10.1016\/j.ajhg.2021.09.007_bib4","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1016\/j.febslet.2006.08.025","article-title":"Functions of the MAPK family in vertebrate-development","volume":"580","author":"Krens","year":"2006","journal-title":"FEBS Lett."},{"key":"10.1016\/j.ajhg.2021.09.007_bib5","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nrn1346","article-title":"MAPK cascade signalling and synaptic plasticity","volume":"5","author":"Thomas","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"10.1016\/j.ajhg.2021.09.007_bib6","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/s41419-019-2075-2","article-title":"Concomitant deletion of HRAS and NRAS leads to pulmonary immaturity, respiratory failure and neonatal death in mice","volume":"10","author":"Fuentes-Mateos","year":"2019","journal-title":"Cell Death Dis."},{"key":"10.1016\/j.ajhg.2021.09.007_bib7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.gde.2020.01.004","article-title":"ERK signaling dynamics in the morphogenesis and homeostasis of Drosophila","volume":"63","author":"Hayashi","year":"2020","journal-title":"Curr. Opin. Genet. Dev."},{"key":"10.1016\/j.ajhg.2021.09.007_bib8","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":"10.1016\/j.ajhg.2021.09.007_bib9","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nrc3106","article-title":"RAS oncogenes: weaving a tumorigenic web","volume":"11","author":"Pylayeva-Gupta","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.ajhg.2021.09.007_bib10","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":"10.1016\/j.ajhg.2021.09.007_bib11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cell.2017.06.009","article-title":"RAS\u00a0proteins and their regulators in human disease","volume":"170","author":"Simanshu","year":"2017","journal-title":"Cell"},{"key":"10.1016\/j.ajhg.2021.09.007_bib12","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1093\/hmg\/1.9.735","article-title":"Analysis of mutations at the neurofibromatosis 1 (NF1) locus","volume":"1","author":"Upadhyaya","year":"1992","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib13","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/ng2113","article-title":"Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype","volume":"39","author":"Brems","year":"2007","journal-title":"Nat. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib14","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.ajhg.2010.06.015","article-title":"Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype","volume":"87","author":"Martinelli","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib15","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/jmedgenet-2015-103018","article-title":"Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome","volume":"52","author":"Yamamoto","year":"2015","journal-title":"J.\u00a0Med. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib16","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.\u00a0Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib17","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1210\/er.2017-00232","article-title":"The RASopathy family: consequences of germline activation of the RAS\/MAPK pathway","volume":"39","author":"Tajan","year":"2018","journal-title":"Endocr. Rev."},{"key":"10.1016\/j.ajhg.2021.09.007_bib18","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/gim.2017.249","article-title":"Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants","volume":"20","author":"Johnston","year":"2018","journal-title":"Genet. Med."},{"key":"10.1016\/j.ajhg.2021.09.007_bib19","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/cge.13533","article-title":"Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome","volume":"95","author":"Pagnamenta","year":"2019","journal-title":"Clin. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib20","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1101\/gr.239186.118","article-title":"Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes","volume":"28","author":"Maher","year":"2018","journal-title":"Genome Res."},{"key":"10.1016\/j.ajhg.2021.09.007_bib21","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1002\/humu.23624","article-title":"Assessing the gene-disease association of 19 genes with the RASopathies using the ClinGen gene curation framework","volume":"39","author":"Grant","year":"2018","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ajhg.2021.09.007_bib22","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.ajhg.2019.04.014","article-title":"Germline-Activating RRAS2 Mutations Cause Noonan Syndrome","volume":"104","author":"Niihori","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib23","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.ajhg.2019.04.013","article-title":"Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome","volume":"104","author":"Capri","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib24","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ajhg.2020.06.018","article-title":"Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum","volume":"107","author":"Motta","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib25","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1101\/gad.341222.120","article-title":"SPRED proteins and their roles in signal transduction, development, and malignancy","volume":"34","author":"Lorenzo","year":"2020","journal-title":"Genes Dev."},{"key":"10.1016\/j.ajhg.2021.09.007_bib26","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1038\/s41436-021-01170-5","article-title":"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation","volume":"23","author":"Legius","year":"2021","journal-title":"Genet. Med."},{"key":"10.1016\/j.ajhg.2021.09.007_bib27","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1093\/emboj\/17.15.4313","article-title":"Structural analysis of the GAP-related domain from neurofibromin and its implications","volume":"17","author":"Scheffzek","year":"1998","journal-title":"EMBO J."},{"key":"10.1016\/j.ajhg.2021.09.007_bib28","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.cell.2007.05.018","article-title":"GEFs and GAPs: critical elements in the control of small G proteins","volume":"129","author":"Bos","year":"2007","journal-title":"Cell"},{"key":"10.1016\/j.ajhg.2021.09.007_bib29","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1086\/498454","article-title":"NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome","volume":"77","author":"De Luca","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib30","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/ejhg.2014.243","article-title":"p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas","volume":"23","author":"Pinna","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib31","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2302\/kjm.2013-0002-RE","article-title":"Legius syndrome, an Update. Molecular pathology of mutations in SPRED1","volume":"62","author":"Brems","year":"2013","journal-title":"Keio J. Med."},{"key":"10.1016\/j.ajhg.2021.09.007_bib32","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1002\/humu.22152","article-title":"Review and update of SPRED1 mutations causing Legius syndrome","volume":"33","author":"Brems","year":"2012","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ajhg.2021.09.007_bib33","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1101\/gad.190876.112","article-title":"A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1","volume":"26","author":"Stowe","year":"2012","journal-title":"Genes Dev."},{"key":"10.1016\/j.ajhg.2021.09.007_bib34","doi-asserted-by":"crossref","first-page":"107909","DOI":"10.1016\/j.celrep.2020.107909","article-title":"Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR","volume":"32","author":"Yan","year":"2020","journal-title":"Cell Rep."},{"key":"10.1016\/j.ajhg.2021.09.007_bib35","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1002\/bies.20632","article-title":"Getting a first clue about SPRED functions","volume":"29","author":"Bundschu","year":"2007","journal-title":"BioEssays"},{"key":"10.1016\/j.ajhg.2021.09.007_bib36","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1042\/BJ20041284","article-title":"Distinct requirements for the Sprouty domain for functional activity of Spred proteins","volume":"388","author":"King","year":"2005","journal-title":"Biochem. J."},{"key":"10.1016\/j.ajhg.2021.09.007_bib37","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/35088082","article-title":"Spred is a Sprouty-related suppressor of Ras signalling","volume":"412","author":"Wakioka","year":"2001","journal-title":"Nature"},{"key":"10.1016\/j.ajhg.2021.09.007_bib38","doi-asserted-by":"crossref","first-page":"7953","DOI":"10.1128\/MCB.22.22.7953-7966.2002","article-title":"The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes","volume":"22","author":"Lim","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"10.1016\/j.ajhg.2021.09.007_bib39","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/S0006-291X(03)00259-6","article-title":"Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation","volume":"302","author":"Kato","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.ajhg.2021.09.007_bib40","doi-asserted-by":"crossref","first-page":"4541","DOI":"10.1128\/MCB.01600-06","article-title":"Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling","volume":"27","author":"Taniguchi","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"10.1016\/j.ajhg.2021.09.007_bib41","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ajhg.2021.01.015","article-title":"SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females","volume":"108","author":"Radio","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib42","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ajhg.2020.11.015","article-title":"SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling","volume":"108","author":"Lin","year":"2021","journal-title":"Am. J. Hum. Genet."},{"issue":"W1","key":"10.1016\/j.ajhg.2021.09.007_bib43","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ajhg.2021.09.007_bib44","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J.\u00a0Mol. Graph."},{"key":"10.1016\/j.ajhg.2021.09.007_bib45","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J.\u00a0Comput. Chem."},{"key":"10.1016\/j.ajhg.2021.09.007_bib46","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S0959-440X(02)00344-5","article-title":"Rotamer libraries in the 21st century","volume":"12","author":"Dunbrack","year":"2002","journal-title":"Curr. Opin. Struct. Biol."},{"key":"10.1016\/j.ajhg.2021.09.007_bib47","doi-asserted-by":"crossref","first-page":"3824","DOI":"10.1093\/hmg\/ddw229","article-title":"SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling","volume":"25","author":"Motta","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib48","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"key":"10.1016\/j.ajhg.2021.09.007_bib49","series-title":"The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio)","author":"Westerfield","year":"2000"},{"key":"10.1016\/j.ajhg.2021.09.007_bib50","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1534\/genetics.114.166769","article-title":"A defined zebrafish line for high-throughput genetics and genomics: NHGRI-1","volume":"198","author":"LaFave","year":"2014","journal-title":"Genetics"},{"key":"10.1016\/j.ajhg.2021.09.007_bib51","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1093\/bfgp\/elr021","article-title":"Lessons from morpholino-based screening in zebrafish","volume":"10","author":"Bedell","year":"2011","journal-title":"Brief. Funct. Genomics"},{"key":"10.1016\/j.ajhg.2021.09.007_bib52","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1371\/journal.pgen.0030078","article-title":"p53 activation by knockdown technologies","volume":"3","author":"Robu","year":"2007","journal-title":"PLoS Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib53","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"10.1016\/j.ajhg.2021.09.007_bib54","doi-asserted-by":"crossref","first-page":"28572","DOI":"10.1074\/jbc.M503640200","article-title":"Gene disruption of Spred-2 causes dwarfism","volume":"280","author":"Bundschu","year":"2005","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.ajhg.2021.09.007_bib55","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1001\/jama.2009.1663","article-title":"Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome","volume":"302","author":"Messiaen","year":"2009","journal-title":"JAMA"},{"key":"10.1016\/j.ajhg.2021.09.007_bib56","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1002\/ajmg.a.33894","article-title":"Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR","volume":"155A","author":"Spencer","year":"2011","journal-title":"Am. J. Med. Genet. A."},{"key":"10.1016\/j.ajhg.2021.09.007_bib57","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1093\/hmg\/ddy412","article-title":"Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling","volume":"28","author":"Motta","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib58","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/s41588-019-0517-5","article-title":"The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy","volume":"51","author":"Lindeboom","year":"2019","journal-title":"Nat. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib59","doi-asserted-by":"crossref","first-page":"3124","DOI":"10.1074\/jbc.M115.703710","article-title":"Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1","volume":"291","author":"Hirata","year":"2016","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.ajhg.2021.09.007_bib60","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s12104-017-9768-1","article-title":"NMR resonance assignments of the EVH1 domain of neurofibromin\u2019s recruitment factor Spred1","volume":"11","author":"F\u00fchrer","year":"2017","journal-title":"Biomol. NMR Assign."},{"key":"10.1016\/j.ajhg.2021.09.007_bib61","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/humu.20005","article-title":"Noonan syndrome-associated SHP2\/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2\/MAPK1 activation","volume":"23","author":"Fragale","year":"2004","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.ajhg.2021.09.007_bib62","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1016\/j.febslet.2006.03.088","article-title":"Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1","volume":"580","author":"Hanna","year":"2006","journal-title":"FEBS Lett."},{"key":"10.1016\/j.ajhg.2021.09.007_bib63","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1093\/hmg\/ddz108","article-title":"Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy","volume":"29","author":"Motta","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib64","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1093\/hmg\/ddp186","article-title":"Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors","volume":"18","author":"Anastasaki","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"10.1016\/j.ajhg.2021.09.007_bib65","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1242\/dmm.007112","article-title":"Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects","volume":"4","author":"Runtuwene","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"10.1016\/j.ajhg.2021.09.007_bib66","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1073\/pnas.1615651114","article-title":"In\u00a0vivo severity ranking of Ras pathway mutations associated with developmental disorders","volume":"114","author":"Jindal","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.ajhg.2021.09.007_bib67","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.yjmcc.2019.01.023","article-title":"SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy","volume":"129","author":"Ullrich","year":"2019","journal-title":"J.\u00a0Mol. Cell. Cardiol."},{"key":"10.1016\/j.ajhg.2021.09.007_bib68","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1111\/cas.13999","article-title":"The Sprouty\/Spred family as tumor suppressors: Coming of age","volume":"110","author":"Kawazoe","year":"2019","journal-title":"Cancer Sci."},{"key":"10.1016\/j.ajhg.2021.09.007_bib69","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/ncb867","article-title":"Sprouty1 and Sprouty2 provide a control mechanism for the Ras\/MAPK signalling pathway","volume":"4","author":"Hanafusa","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"10.1016\/j.ajhg.2021.09.007_bib70","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1074\/jbc.M108368200","article-title":"Sprouty2 inhibits the Ras\/MAP kinase pathway by inhibiting the activation of Raf","volume":"277","author":"Yusoff","year":"2002","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.ajhg.2021.09.007_bib71","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00418-004-0725-6","article-title":"Expression and subcellular localization of Spred proteins in mouse and human tissues","volume":"122","author":"Engelhardt","year":"2004","journal-title":"Histochem. Cell Biol."},{"key":"10.1016\/j.ajhg.2021.09.007_bib72","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1084\/jem.20040616","article-title":"Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness","volume":"201","author":"Inoue","year":"2005","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.ajhg.2021.09.007_bib73","doi-asserted-by":"crossref","first-page":"14443","DOI":"10.1523\/JNEUROSCI.4698-08.2008","article-title":"Spred1 is required for synaptic plasticity and hippocampus-dependent learning","volume":"28","author":"Denayer","year":"2008","journal-title":"J.\u00a0Neurosci."},{"key":"10.1016\/j.ajhg.2021.09.007_bib74","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/nm1084","article-title":"Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation","volume":"10","author":"Araki","year":"2004","journal-title":"Nat. Med."},{"key":"10.1016\/j.ajhg.2021.09.007_bib75","doi-asserted-by":"crossref","first-page":"16395","DOI":"10.1073\/pnas.1418126111","article-title":"K-RasV14I recapitulates Noonan syndrome in mice","volume":"111","author":"Hern\u00e1ndez-Porras","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.ajhg.2021.09.007_bib76","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1172\/JCI44929","article-title":"MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation","volume":"121","author":"Wu","year":"2011","journal-title":"J.\u00a0Clin. Invest."},{"key":"10.1016\/j.ajhg.2021.09.007_bib77","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/mp.2016.232","article-title":"OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB\/ERK-MAPK signaling as a result of SPRED2 deficiency","volume":"23","author":"Ullrich","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"10.1016\/j.ajhg.2021.09.007_bib78","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.ajhg.2013.04.008","article-title":"Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism","volume":"92","author":"Miraoui","year":"2013","journal-title":"Am. J. Hum. Genet."}],"container-title":["The American Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002929721003438?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002929721003438?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T07:22:38Z","timestamp":1757575358000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0002929721003438"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":78,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["S0002929721003438"],"URL":"https:\/\/doi.org\/10.1016\/j.ajhg.2021.09.007","relation":{},"ISSN":["0002-9297"],"issn-type":[{"value":"0002-9297","type":"print"}],"subject":[],"published":{"date-parts":[[2021,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype","name":"articletitle","label":"Article Title"},{"value":"The American Journal of Human Genetics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ajhg.2021.09.007","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 American Society of Human Genetics.","name":"copyright","label":"Copyright"}]}}