{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T07:49:20Z","timestamp":1762674560603,"version":"3.41.2"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by unique osteosclerosis of the long tubular bones and platyspondyly. DOS is inherited in an autosomal recessive manner and is genetically and clinically heterogeneous. To date, four individuals with DOS who have five different <jats:italic>TNFRSF11A<\/jats:italic> mutations have been reported. Based on their data, it is hypothesized that mutations producing aberrant mutant RANK proteins (missense or truncated or elongated) cause DOS, while null mutations lead to osteopetrosis, autosomal recessive 7 (OPTB7). Herein, we present the fifth case of <jats:italic>TNFRSF11A<\/jats:italic>-associated DOS with a novel homozygous frame-shift mutation (c.19_31del; p.[Arg7CysfsTer172]). The mutation is predicted to cause nonsense mutation-mediated mRNA decay (NMD) in all RANK isoform transcripts, resulting in totally null allele. Our findings suggest genotype-phenotype relationship in <jats:italic>TNFRSF11A<\/jats:italic>-associated OPTB7 and DOS remains unclear, and that the deficiency of <jats:italic>TNFRSF11A<\/jats:italic> functions might cause DOS, rather than osteopetrosis. More data are necessary to understand the phenotypic spectrum caused by <jats:italic>TNFRSF11A<\/jats:italic> mutations.<\/jats:p>","DOI":"10.3389\/fgene.2022.938814","type":"journal-article","created":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T07:10:16Z","timestamp":1656054616000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Tar\u0131k","family":"K\u0131rkg\u00f6z","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Behzat","family":"\u00d6zkan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filiz","family":"Hazan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sezer","family":"Acar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00d6zlem","family":"Nalbanto\u011flu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beyhan","family":"\u00d6zkaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melike Ataseven","family":"Kulal\u0131","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Semra","family":"G\u00fcrsoy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiro","family":"Ikegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1002\/jbmr.4288","article-title":"Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice","volume":"36","author":"Alonso","year":"2021","journal-title":"J Bone & Mineral Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4904","DOI":"10.1093\/hmg\/dds326","article-title":"Whole-exome Sequencing Identifies Mutations in the Nucleoside Transporter Gene SLC29A3 in Dysosteosclerosis, a Form of Osteopetrosis","volume":"21","author":"Campeau","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1136\/jmg.39.8.603","article-title":"Dysosteosclerosis: a Report of Three New Cases and Evolution of the Radiological Findings","volume":"39","author":"El\u00e7ioglu","year":"2002","journal-title":"J. Med. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/77131","article-title":"Defects in TCIRG1 Subunit of the Vacuolar Proton Pump Are Responsible for a Subset of Human Autosomal Recessive Osteopetrosis","volume":"25","author":"Frattini","year":"2000","journal-title":"Nat. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.ajhg.2008.06.015","article-title":"Human Osteoclast-Poor Osteopetrosis with Hypogammaglobulinemia Due to TNFRSF11A (RANK) Mutations","volume":"83","author":"Guerrini","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.ajhg.2019.03.004","article-title":"Bi-Allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation","volume":"104","author":"Guo","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/s10038-018-0447-6","article-title":"Dysosteosclerosis Is Also Caused by TNFRSF11A Mutation","volume":"63","author":"Guo","year":"2018","journal-title":"J. Hum. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"988","DOI":"10.2214\/ajr.130.5.988","article-title":"Dysosteosclerosis","volume":"130","author":"Houston","year":"1978","journal-title":"Am. J. Roentgenol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.bone.2018.12.002","article-title":"Sclerosing Bone Dysplasias with Hallmarks of Dysosteosclerosis in Four Patients Carrying Mutations in SLC29A3 and TCIRG1","volume":"120","author":"Howaldt","year":"2019","journal-title":"Bone"},{"key":"B10","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1002\/jbmr.559","article-title":"RANK\u2010dependent Autosomal Recessive Osteopetrosis: Characterization of Five New Cases with Novel Mutations","volume":"27","author":"Pangrazio","year":"2012","journal-title":"J. Bone Min. Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: a Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1002\/ajmg.c.31937","article-title":"Molecular Diagnosis in a Cohort of 114 Patients with Rare Skeletal Dysplasias","volume":"187","author":"Silveira","year":"2021","journal-title":"Am. J. Med. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1055\/s-0029-1228480","article-title":"Die Dysosteosklerose - eine Sonderform der generalisierten Osteosklerose","volume":"109","author":"Spranger","year":"1968","journal-title":"Fortschr R\u00f6ntgenstr"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.1002\/ajmg.a.62198","article-title":"Resolution of Sclerotic Lesions of Dysosteosclerosis Due to Biallelic SLC29A3 Variant in a Turkish Girl","volume":"185","author":"Uluda\u011f Alkaya","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1002\/jbmr.131","article-title":"Dysosteosclerosis Presents as an \"Osteoclast-Poor\" Form of Osteopetrosis: Comprehensive Investigation of a 3-Year-Old Girl and Literature Review","volume":"25","author":"Whyte","year":"2010","journal-title":"J. Bone Min. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1186\/s12893-021-01266-4","article-title":"A Novel Mutation in TNFRSF11A Gene Causes Pediatric Osteopetrosis: Case Report","volume":"21","author":"Xu","year":"2021","journal-title":"BMC Surg."},{"key":"B17","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s00774-020-01148-4","article-title":"Genetic Disorders Associated with the RANKL\/OPG\/RANK Pathway","volume":"39","author":"Xue","year":"2021","journal-title":"J. Bone Min. Metab."},{"key":"B18","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/s10038-020-00891-w","article-title":"Expanding the Phenotypic Spectrum of TNFRSF11A-Associated Dysosteosclerosis: a Case with Intracranial Extramedullary Hematopoiesis","volume":"66","author":"Xue","year":"2021","journal-title":"J. Hum. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s10038-020-00831-8","article-title":"The Third Case of TNFRSF11A-Associated Dysosteosclerosis with a Mutation Producing Elongating Proteins","volume":"9","author":"Xue","year":"2020","journal-title":"J. Hum. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1002\/jbmr.3805","article-title":"TNFRSF11A \u2010Associated Dysosteosclerosis: A Report of the Second Case and Characterization of the Phenotypic Spectrum","volume":"34","author":"Xue","year":"2019","journal-title":"J. Bone Min. Res."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.938814\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T07:10:18Z","timestamp":1656054618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.938814\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,24]]},"references-count":20,"alternative-id":["10.3389\/fgene.2022.938814"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.938814","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2022,6,24]]},"article-number":"938814"}}