{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:20:12Z","timestamp":1788315612590,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2015,6,11]],"date-time":"2015-06-11T00:00:00Z","timestamp":1433980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH R01\u2010AR41916"],"award-info":[{"award-number":["NIH R01\u2010AR41916"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:sec><jats:label\/><jats:p>Severe variants of fibrodysplasia ossificans progressiva (FOP) affect &lt;2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype\u2013genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female). Both children had an identical mutation in<jats:italic>ACVR1<\/jats:italic>c.772A&gt;G; p.Arg258Gly (R258G), not previously described in FOP. Although many, if not most, FOP mutations directly perturb the structure of the GS regulatory subdomain and presumably the adjacent \u03b1C helix, substitution with glycine at R258 may directly alter the position of the helix in the kinase domain, eliminating a key aspect of the autoinhibitory mechanism intrinsic to the wild\u2010type ACVR1 kinase. The high fidelity phenotype\u2013genotype relationship in these unrelated children with the most severe FOP phenotype reported to date suggests that the shared features are due to the dysregulated activity of the mutant kinase during development and postnatally, and provides vital insight into the structural biology and function of ACVR1 as well as the design of small molecule inhibitors. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.37205","type":"journal-article","created":{"date-parts":[[2015,6,19]],"date-time":"2015-06-19T17:12:10Z","timestamp":1434733930000},"page":"2265-2271","source":"Crossref","is-referenced-by-count":39,"title":["Multi\u2010system involvement in a severe variant of fibrodysplasia ossificans progressiva (<i>ACVR1<\/i>c.772G&gt;A; R258G): A report of two patients"],"prefix":"10.1002","volume":"167","author":[{"given":"Frederick S.","family":"Kaplan","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Department ofMedicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce A.","family":"Kobori","sequence":"additional","affiliation":[{"name":"Department of Genetics, The Permanente Medical Group, Inc. San Jose California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Orellana","sequence":"additional","affiliation":[{"name":"Unidad de Genetica y Diagnostico Prenatal, Hospital Universitario y Politecnio La Fe Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Calvo","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology, Hospital Universitario y Politecnio La Fe Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Rosello","sequence":"additional","affiliation":[{"name":"Unidad de Genetica y Diagnostico Prenatal, Hospital Universitario y Politecnio La Fe Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Martinez","sequence":"additional","affiliation":[{"name":"Unidad de Genetica y Diagnostico Prenatal, Hospital Universitario y Politecnio La Fe Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Lopez","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology, Hospital Universitario y Politecnio La Fe Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Department ofMedicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Pignolo","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Department ofMedicine, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen M.","family":"Shore","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"},{"name":"The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Department ofGenetics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay C.","family":"Groppe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Texas A&amp;M University Baylor College of Dentistry Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,6,11]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.178"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.365932"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.15.6.946"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1633"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1159\/000324230"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1159\/000365770"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-169x.2004.00783.x"},{"key":"e_1_2_5_9_1","first-page":"275","article-title":"The conformational plasticity of protein kinases","volume":"109","author":"Huse M","year":"2002","journal-title":"Mol Cell"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3811"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-012-6563-x"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2009.10.006"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20868"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.010280"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1517\/21678707.2013.825208"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0636"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2013.03.017"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/den353"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2012.07.002"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-80"},{"key":"e_1_2_5_21_1","first-page":"437","article-title":"Fibrodysplasia ossificans progressiva: Diagnosis, management, and therapeutic horizons. 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