Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia.
Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia.
复制标题
DOI：
10.1186/s13630-017-0051-y
复制
发表时间：
2017-01-01
期刊：
影响因子：
--
通讯作者：
Krakow, Deborah
中科院分区：
文献类型：
--
作者：
Duran, Ivan;Taylor, S Paige;Krakow, Deborah
背景：骨骼纤毛病变包括一系列对骨骼有深远影响的纤毛功能障碍。这些疾病中最常见的是短肋多指综合征（SRPS），这是一种复发性遗传的围产期致死性疾病，其特征是胸部狭长、长骨明显缩短、多指（趾），并且通常累及多器官系统。SRPS显示出广泛的基因座异质性，编码参与纤毛形成和/或功能的蛋白质的基因发生突变。结果：在本文中，我们描述了逆行IFT-A复合物的卫星成员IFT 43的突变，该突变产生了一种具有异常弯曲的SRPS形式肋骨和附肢骨。这些新描述的IFFT 43突变破坏纤毛形成，产生软骨生长板结构异常，从而导致改变的软骨内骨化。我们进一步表明，IFFT 43 SRPS表型与SRPS相似，这是由于编码IFFT 121（WDR 35）的基因突变所致，该基因与IFFT 43直接相互作用。结论：本研究定义了一种新的IFFT 43相关表型，确定了一个额外的SRPS位点。数据表明，IFFT 43是纤毛发生所必需的，并且突变破坏了生长板软骨细胞的有序增殖和分化，导致对软骨内骨化和矿化的严重影响。与SRPS的表型相似性的情况下，在基因编码的IFFT 43直接相互作用蛋白IFFT 121的突变表明，类似的机制可能会被破坏的缺陷，这两个IFFT-A卫星相互作用。
BACKGROUND: Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function.RESULTS: Herein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43.CONCLUSIONS: This study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors.