Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling
Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling
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DOI：
10.1016/j.ajhg.2012.02.005
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发表时间：
2012-03-09
影响因子：
9.8
通讯作者：
Krakow, Deborah
中科院分区：
文献类型：
--
作者：
Merrill, Amy E.;Sarukhanov, Anna;Krakow, Deborah
成纤维细胞生长因子受体2（FGFR2）是胚胎发育过程中骨形成的重要调节因子。在小鼠中的获得和丧失功能的研究都表明，FGFR 2在骨祖细胞的增殖和分化之间维持关键平衡。我们已经确定了偶发性围产期致死性骨骼发育不良的新发FGFR2突变，其特征为颅骨矿化不良、颅缝早闭、畸形面部特征、产前牙齿、耻骨和锁骨发育不全、骨质减少和长骨弯曲。长骨的组织学分析显示，生长板含有较小的肥大软骨细胞和增厚的多细胞骨膜。发现4个无关的受影响个体为错义突变杂合子，错义突变将极性氨基酸引入FGFR 2的疏水跨膜结构域。使用患病的软骨细胞和基于细胞的测定，我们确定这些突变选择性地降低FGFR2的质膜水平，并显着降低受体对细胞外FGF的反应性。总之，这些临床和分子学发现与先前表征的FGFR 2疾病不同，代表了独特的骨骼发育不良。
Fibroblast growth factor receptor 2 (FGFR2) is a crucial regulator of bone formation during embryonic development. Both gain and loss-of-function studies in mice have shown that FGFR2 maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells. We have identified de novo FGFR2 mutations in a sporadically occurring perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Histological analysis of the long bones revealed that the growth plate contained smaller hypertrophic chondrocytes and a thickened hypercellular periosteum. Four unrelated affected individuals were found to be heterozygous for missense mutations that introduce a polar amino acid into the hydrophobic transmembrane domain of FGFR2. Using diseased chondrocytes and a cell-based assay, we determined that these mutations selectively reduced plasma-membrane levels of FGFR2 and markedly diminished the receptor's responsiveness to extracellular FGF. All together, these clinical and molecular findings are separate from previously characterized FGFR2 disorders and represent a distinct skeletal dysplasia.