{"doi":"10.1016/j.bone.2024.117085","title":"Skeletal abnormalities in mice with Dnmt3a missense mutations","abstract":"Overgrowth and intellectual disability disorders in humans are typified by length/height and/or head circumference ≥ 2 standard deviations above the mean as well as intellectual disability and behavioral comorbidities, including autism and anxiety. Tatton-Brown-Rahman Syndrome is one type of overgrowth and intellectual disability disorder caused by heterozygous missense mutations in the DNA methyltransferase 3A ( DNMT3A ) gene. Numerous DNMT3A mutations have been identified in Tatton-Brown-Rahman Syndrome patients and may be associated with varying phenotype severities of clinical presentation. Two such mutations are the R882H and P904L mutations which result in severe and mild phenotypes, respectively. Mice with paralogous mutations ( Dnmt3a P900L /+ and Dnmt3a R878H /+ ) exhibit overgrowth in their long bones (e.g., femur, humerus), but the mechanisms responsible for their skeletal overgrowth remain unknown. The goal of this study is to characterize skeletal phenotypes in mouse models of Tatton-Brown-Rahman Syndrome and identify potential cellular mechanisms involved in the skeletal overgrowth phenotype. We report that mature mice with the Dnmt3a P900L /+ or Dnmt3a R878H /+ mutation exhibit tibial overgrowth, cortical bone thinning, and weakened bone mechanical properties. Dnmt3a R878H /+ mutants also contain larger bone marrow adipocytes while Dnmt3a P900L /+ mutants show no adipocyte phenotype compared to control animals. To understand the potential cellular mechanisms regulating these phenotypes, growth plate chondrocytes , osteoblasts , and osteoclasts were assessed in juvenile mutant mice using quantitative static histomorphometry and dynamic histomorphometry. Tibial growth plates appeared thicker in mutant juvenile mice, but no changes were observed in osteoblast activity or osteoclast number in the femoral mid-diaphysis. These studies reveal new skeletal phenotypes associated with Tatton-Brown-Rahman Syndrome in mice and provide a rationale to extend clinical assessments of patients with this condition to include bone density and quality testing. These findings may be also informative for skeletal characterization of other mouse models presenting with overgrowth and intellectual disability phenotypes. • Genetic mouse models of Tatton-Brown-Rahman Syndrome recapitulate bone phenotypes. • Heterozygous mutations in Dnmt3a cause long bone overgrowth and cortical thinning. • Bone mechanical properties are compromised in Dnmt3a mutants. • Bone marrow adipose tissue is upregulated in mice with the Dnmt3a R878H /+ mutation. • Juvenile mice with mutations in Dnmt3a exhibit growth plate thickening.","journal":"Bone","year":2024,"id":465133,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1065633,"name":"Diana C. Beard","orcid":"0000-0002-1799-0771","position":1,"is_corresponding":false},{"id":1296630,"name":"Kathryn Feeney","orcid":null,"position":2,"is_corresponding":false},{"id":391778,"name":"Hongjun Zheng","orcid":null,"position":3,"is_corresponding":false},{"id":1296258,"name":"Yunhao Jiang","orcid":"0000-0002-2528-1174","position":4,"is_corresponding":false},{"id":323593,"name":"Xiyun Zhang","orcid":"0000-0002-7694-234X","position":5,"is_corresponding":false},{"id":1296259,"name":"Jin Liu","orcid":"0000-0001-5816-2422","position":6,"is_corresponding":false},{"id":290777,"name":"Harrison W. Gabel","orcid":"0000-0001-6894-5113","position":7,"is_corresponding":false},{"id":291413,"name":"Audrey McAlinden","orcid":"0000-0001-8433-4224","position":8,"is_corresponding":false},{"id":291412,"name":"Austin Bell‐Hensley","orcid":"0000-0003-1498-3012","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:04:46.201722Z","pmid":"38522809","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}