Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California.
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Dev Dyn. 2019 Mar;248(3):233-246. doi: 10.1002/dvdy.9. Epub 2019 Jan 28.
Bent bone dysplasia syndrome (BBDS), a congenital skeletal disorder caused by dominant mutations in fibroblast growth factor receptor 2 (FGFR2), is characterized by bowed long bones within the limbs. We previously showed that the FGFR2 mutations in BBDS enhance nuclear and nucleolar localization of the receptor; however, exactly how shifts in subcellular distribution of FGFR2 affect limb development remained unknown.
Targeted expression of the BBDS mutations in the lateral plate mesoderm of the developing chick induced angulated hindlimbs, a hallmark feature of the disease. Whole-mount analysis of the underlying skeleton revealed bent long bones with shortened bone collars and, in severe cases, dysmorphic epiphyses. Epiphyseal changes were also correlated with joint dislocations and contractures. Histological analysis revealed that bent long bones and joint defects were closely associated with irregularities in skeletal muscle patterning and tendon-to-bone attachment. The spectrum of limb phenotypes induced by the BBDS mutations were recapitulated by targeted expression of wild-type FGFR2 appended with nuclear and nucleolar localization signals.
Our results indicate that the bent long bones in BBDS arise from disruptions in musculoskeletal integration and that increased nuclear and nucleolar localization of FGFR2 plays a mechanistic role in the disease phenotype. 248:233-246, 2019. © 2018 Wiley Periodicals, Inc.
弯曲骨发育不良综合征（BBDS）是一种由成纤维细胞生长因子受体 2（FGFR2）的显性突变引起的先天性骨骼疾病，其特征是四肢的长骨弯曲。我们之前的研究表明，BBDS 中的 FGFR2 突变增强了受体的核和核仁定位；然而，FGFR2 亚细胞分布的变化如何影响肢体发育仍不清楚。
在发育中的鸡的侧板中胚层中靶向表达 BBDS 突变会导致后肢弯曲，这是该疾病的一个显著特征。对底层骨骼的全器官分析显示，长骨弯曲，骨颈缩短，在严重的情况下，骺端畸形。骺端变化也与关节脱位和挛缩有关。组织学分析表明，弯曲的长骨和关节缺陷与骨骼肌模式和肌腱与骨骼附着的不规则密切相关。野生型 FGFR2 与核和核仁定位信号连接后的靶向表达再现了 BBDS 突变所诱导的肢体表型谱。
我们的结果表明，BBDS 中的弯曲长骨是由于肌肉骨骼整合的中断引起的，并且 FGFR2 的核和核仁定位增加在疾病表型中起着机制作用。248:233-246, 2019. © 2018 Wiley Periodicals, Inc.
