PDF(Pubmed)
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 (Dnmt3aP900L/+ and Dnmt3aR878H/+) 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 Dnmt3aP900L/+ or Dnmt3aR878H/+ mutation exhibit tibial overgrowth, cortical bone thinning, and weakened bone mechanical properties. Dnmt3aR878H/+ mutants also contain larger bone marrow adipocytes while Dnmt3aP900L/+ 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.
摘要：
人类的过度生长和智力障碍障碍以长度/身高和/或头围≥平均值以上2个标准偏差以及智力障碍和行为合并症为代表，包括自闭症和焦虑。Tatton-Brown-Rahman综合征是一种由DNA甲基转移酶3A（DNMT3A）基因的杂合错义突变引起的过度生长和智力障碍。已经在Tatton-Brown-Rahman综合征患者中鉴定了许多DNMT3A突变，并且可能与临床表现的不同表型严重程度有关。两个这样的突变是导致严重和轻度表型的R882H和P904L突变。分别。具有旁系同源突变的小鼠（Dnmt3aP900L/和Dnmt3aR878H/）在其长骨中表现出过度生长（例如，股骨,肱骨),但其骨骼过度生长的机制尚不清楚。这项研究的目的是表征Tatton-Brown-Rahman综合征小鼠模型中的骨骼表型，并确定参与骨骼过度生长表型的潜在细胞机制。我们报道，具有Dnmt3aP900L/+或Dnmt3aR878H/+突变的成熟小鼠表现出胫骨过度生长，皮质骨变薄，和削弱骨的力学性能。与对照动物相比,Dnmt3aR878H/+突变体还含有较大的骨髓脂肪细胞,而Dnmt3aP900L/+突变体没有显示脂肪细胞表型。为了了解调节这些表型的潜在细胞机制，生长板软骨细胞，成骨细胞，使用定量静态组织形态计量学和动态组织形态计量学在幼年突变小鼠中评估破骨细胞。突变幼鼠的胫骨生长板显得较厚,但未观察到股骨中骨干的成骨细胞活性或破骨细胞数量的变化。这些研究揭示了小鼠中与Tatton-Brown-Rahman综合征相关的新骨骼表型，并提供了扩展对患有这种疾病的患者的临床评估以包括骨密度和质量测试的基本原理。这些发现也可能为表现出过度生长和智力障碍表型的其他小鼠模型的骨骼表征提供信息。
