{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:35:49Z","timestamp":1785818149798,"version":"3.56.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2022,3,26]],"date-time":"2022-03-26T00:00:00Z","timestamp":1648252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Joint Program on Rare Diseases"},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 21614"],"award-info":[{"award-number":["IG 21614"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health","award":["CCR-2017-23669081"],"award-info":[{"award-number":["CCR-2017-23669081"]}]},{"name":"Italian Ministry of Health","award":["RCR-2020-23670068_001"],"award-info":[{"award-number":["RCR-2020-23670068_001"]}]},{"name":"Italian Ministry of Health","award":["FR-2018-12366931"],"award-info":[{"award-number":["FR-2018-12366931"]}]},{"name":"Italian Ministry of Research"},{"name":"German Federal Ministry of Education and Research","award":["01GM1902A"],"award-info":[{"award-number":["01GM1902A"]}]},{"name":"European Reference Network on Rare Congenital Malformations"},{"name":"Rare Intellectual Disability"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,23]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A\u2009&amp;gt;\u2009G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A\u2009&amp;gt;\u2009G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddac071","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T12:11:15Z","timestamp":1647864675000},"page":"2766-2778","source":"Crossref","is-referenced-by-count":24,"title":["Expanding the molecular spectrum of pathogenic<i>SHOC2<\/i>variants underlying Mazzanti syndrome"],"prefix":"10.1093","volume":"31","author":[{"given":"Marialetizia","family":"Motta","sequence":"first","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS , 00146 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Solman","sequence":"additional","affiliation":[{"name":"Hubrecht Institute-KNAW and University Medical Center Utrecht , 3584 Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline A","family":"Bonnard","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique, Assistance Publique des H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Robert Debr\u00e9 , 75019 Paris , France"},{"name":"INSERM UMR 1131 , Institut de Recherche Saint-Louis, , 75010 Paris , France"},{"name":"Universit\u00e9 de Paris , Institut de Recherche Saint-Louis, , 75010 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma","family":"Kuechler","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Humangenetik, Universit\u00e4tsklinikum Essen, Universit\u00e4t Duisburg-Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pantaleoni","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS , 00146 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Priolo","sequence":"additional","affiliation":[{"name":"UOSD Genetica Medica, Grandeospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d , 89124 Reggio Calabria , Italia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balasubramanian","family":"Chandramouli","sequence":"additional","affiliation":[{"name":"Super Computing Applications and Innovation, CINECA , 40033 Bologna , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Coppola","sequence":"additional","affiliation":[{"name":"National Centre Rare Diseases, Istituto Superiore di Sanit\u00e0 , 00161 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Pizzi","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS , 00146 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Zara","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS , 00146 Rome , Italy"},{"name":"Department of Biology and Biotechnology \u201cCharles Darwin\u201d, Sapienza University of Rome , 00185 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ferilli","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS , 00146 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00fclya","family":"Kayserili","sequence":"additional","affiliation":[{"name":"Genetic Diseases Evaluation Center , Medical Genetics Department, , \u0130stanbul 34010 , Turkey"},{"name":"Ko\u00e7 University School of Medicine , Medical Genetics Department, , \u0130stanbul 34010 , Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Onesimo","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defects , Department of Woman and Child Health and Public Health, , 00168 Rome , Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli, IRCCS , Department of Woman and Child Health and Public Health, , 00168 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defects , Department of Woman and Child Health and Public Health, , 00168 Rome , Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli, IRCCS , Department of Woman and Child Health and Public Health, , 00168 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Brinkmann","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Magdeburg , 39120 Magdeburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1437-0427","authenticated-orcid":false,"given":"Yoann","family":"Vial","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique, Assistance Publique des H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Robert Debr\u00e9 , 75019 Paris , France"},{"name":"INSERM UMR 1131 , Institut de Recherche Saint-Louis, , 75010 Paris , France"},{"name":"Universit\u00e9 de Paris , Institut de Recherche Saint-Louis, , 75010 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne B","family":"Kamphausen","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Magdeburg , 39120 Magdeburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Thomas-Teinturier","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Assistance Publique-H\u00f4pitaux de Paris, Universit\u00e9 Paris-Saclay, H\u00f4pital Bic\u00eatre , 94270 Le Kremlin Bic\u00eatre , France"},{"name":"INSERM UMR 1018, Cancer and Radiation Team, CESP , 94800 Villejuif , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Guimier","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine Genomique des Maladies Rares, CRMR Anomalies du d\u00e9veloppement, H\u00f4pital Necker-Enfants Malades, Assistance Publique des H\u00f4pitaux de Paris , 75015 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Cordeddu","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0 , 00161 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"Alma Mater Studiorum, University of Bologna , 40125 Bologna , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defects , Department of Woman and Child Health and Public Health, , 00168 Rome , Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli, IRCCS , Department of Woman and Child Health and Public Health, , 00168 Rome , Italy"},{"name":"Department of Woman and Child Health and Public Health, Universit\u00e0 Cattolica del Sacro Cuore , 00168 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Chillemi","sequence":"additional","affiliation":[{"name":"Department for Innovation in Biological, Agro-food and Forest systems, Universit\u00e0 della Tuscia , 01100 Viterbo , Italy"},{"name":"Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari, Centro Nazionale delle Ricerche , 70126 Bari , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Zenker","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Humangenetik, Universit\u00e4tsklinikum Essen, Universit\u00e4t Duisburg-Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Cav\u00e9","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique, Assistance Publique des H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Robert Debr\u00e9 , 75019 Paris , France"},{"name":"INSERM UMR 1131 , Institut de Recherche Saint-Louis, , 75010 Paris , France"},{"name":"Universit\u00e9 de Paris , Institut de Recherche Saint-Louis, , 75010 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"den Hertog","sequence":"additional","affiliation":[{"name":"Hubrecht Institute-KNAW and University Medical Center Utrecht , 3584 Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS , 00146 Rome , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,26]]},"reference":[{"key":"2022082420172663600_ref1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/ajmg.a.10923","article-title":"Noonan-like syndrome with loose anagen hair: a new syndrome?","volume":"118A","author":"Mazzanti","year":"2003","journal-title":"Am. 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