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首页> 外文期刊>Cilia >Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia
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Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

机译：IFT-A卫星核心成分基因IFT43和IFT121的突变产生短肋多指综合征，并带有独特的坎波米亚病

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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.
机译：背景骨骼纤毛病包括一系列对骨骼有深远影响的睫状功能障碍疾病。在这些疾病中，最常见的是短肋多指综合征（SRPS），一种隐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，而且常常累及多器官系统。 SRPS显示出广泛的基因座异质性，其中编码参与纤毛形成和/或功能的蛋白质的基因突变。结果在本文中，我们描述了IFT43（逆行IFT-A复合体的卫星成员）中的突变，该突变产生一种形式的SRPS，肋骨和阑尾骨骼异常弯曲。这些新描述的IFT43突变破坏了纤毛的形成，在软骨生长板结构中产生了异常，从而促进了软骨内骨化的改变。我们进一步表明，IFT43 SRPS表型类似于由编码IFT121（WDR35）（与IFT43的直接相互作用因子）的基因突变产生的SRPS。结论这项研究定义了一种新的IFT43相关表型，为SRPS确定了另一个基因座。数据表明IFT43是纤毛形成所必需的，并且该突变破坏了生长板软骨细胞的有序增殖和分化，从而对软骨内骨化和矿化产生了严重影响。由编码IFT43直接相互作用蛋白IFT121的基因突变产生的与SRPS病例的表型相似性表明，这两个IFT-A卫星相互作用子中的缺陷可能会破坏相似的机制。

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