{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:40:42Z","timestamp":1790419242956,"version":"4.1.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2014,6,16]],"date-time":"2014-06-16T00:00:00Z","timestamp":1402876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic biallelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates that pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant overexpression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing. \u00a9 2014 American Society for Bone and Mineral Research<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2298","type":"journal-article","created":{"date-parts":[[2014,6,17]],"date-time":"2014-06-17T00:13:28Z","timestamp":1402964008000},"page":"2636-2642","source":"Crossref","is-referenced-by-count":31,"title":["Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1"],"prefix":"10.1093","volume":"29","author":[{"given":"Nandina","family":"Paria","sequence":"first","affiliation":[{"name":"Sarah M. and Charles E. Seay Center for Musculoskeletal ResearchTexas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Joon","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Pediatric OrthopaedicsSeoul National University Children's HospitalSeoulRepublic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Ho","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Pediatric OrthopaedicsSeoul National University Children's HospitalSeoulRepublic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Kamiya","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryUT Southwestern Medical CenterDallasTXUSA"},{"name":"Sarah M. and Charles E. Seay Center for Musculoskeletal ResearchTexas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Kayembe","sequence":"additional","affiliation":[{"name":"Baylor Institute for Immunology ResearchDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of PathologyUniversity of Utah Medical SchoolSalt Lake CityUTUSA"},{"name":"ARUP Institute for Clinical and Experimental PathologyARUP LaboratoriesSalt Lake CityUTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L","family":"Margraf","sequence":"additional","affiliation":[{"name":"ARUP Institute for Clinical and Experimental PathologyARUP LaboratoriesSalt Lake CityUTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerlinde","family":"Obermosser","sequence":"additional","affiliation":[{"name":"Baylor Institute for Immunology ResearchDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ila","family":"Oxendine","sequence":"additional","affiliation":[{"name":"Sarah M. and Charles E. Seay Center for Musculoskeletal ResearchTexas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W","family":"Sant","sequence":"additional","affiliation":[{"name":"ARUP Institute for Clinical and Experimental PathologyARUP LaboratoriesSalt Lake CityUTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Hyun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryJeju National University HospitalJejuRepublic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Department of PediatricsDivision of Medical GeneticsUniversity of UtahSalt Lake CityUTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H","family":"Viskochil","sequence":"additional","affiliation":[{"name":"Department of PediatricsDivision of Medical GeneticsUniversity of UtahSalt Lake CityUTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A","family":"Wise","sequence":"additional","affiliation":[{"name":"Eugene McDermott Center for Human Growth and DevelopmentUT Southwestern Medical CenterDallasTXUSA"},{"name":"Department of PediatricsUT Southwestern Medical CenterDallasTXUSA"},{"name":"Department of Orthopaedic SurgeryUT Southwestern Medical CenterDallasTXUSA"},{"name":"Sarah M. and Charles E. Seay Center for Musculoskeletal ResearchTexas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry KW","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryUT Southwestern Medical CenterDallasTXUSA"},{"name":"Sarah M. and Charles E. Seay Center for Musculoskeletal ResearchTexas Scottish Rite Hospital for ChildrenDallasTXUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J","family":"Rios","sequence":"additional","affiliation":[{"name":"Eugene McDermott Center for Human Growth and DevelopmentUT Southwestern Medical CenterDallasTXUSA"},{"name":"Department of PediatricsUT Southwestern Medical CenterDallasTXUSA"},{"name":"Department of Orthopaedic SurgeryUT Southwestern Medical CenterDallasTXUSA"},{"name":"Sarah M. and Charles E. 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