A rare TTC30B variant is identified as a candidate for synpolydactyly in a Chinese pedigree
A rare TTC30B variant is identified as a candidate for synpolydactyly in a Chinese pedigree
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DOI：
10.1016/j.bone.2019.07.012
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发表时间：
2019-10-01
期刊：
影响因子：
4.1
通讯作者：
Wan, Shengxiang
中科院分区：
文献类型：
--
作者：
Du, Ye;Chen, Fangfang;Wan, Shengxiang
背景：II型并指畸形（synpolydactyly， SPD）是一种罕见的常染色体显性遗传病，不完全外显率较高。目前，HOXD13的几个变异和FBLN1的一个缺失与SPD有关。然而，几个SPD家族的致病变异及其病因机制在很大程度上仍然未知。方法：采用全外显子组和PCR-sanger测序，并结合两点连锁分析，鉴定中国6代家系的致病变异。同源性建模结合RNAi和qRT-PCR实验揭示TTC30B变异的致病机制。结果：报告了6代SPD家族。本家族患者除SPD外无其他临床畸形。一种罕见的错义变体c.1157C > T [p]。TTC30B中的Ala375Val [chr2:178416368， hg19]被证明是SPD家族的主要基因。模型结构表明，Ala375在进化和结构上都是保守的。预测变异p.a ala375val对蛋白质结构和/或稳定性有害。两点连锁分析的最大LOD评分为3.1444 （P = 0.000071）。此外，我们发现TTC30B受Shh信号通路的调控，TTC30B的异常表达会影响人视网膜色素上皮细胞Shh信号通路的激活。结论：本研究首次证实IFT（纤束内运输）相关基因TTC30B与SPD有关。
Background: Syndactyly type II (synpolydactyly, SPD) is a rare autosomal dominant inherited disease with higher incomplete penetrance. Currently, several variants in HOXD13 and one deletion in FBLN1 have been associated with SPD. However, the causative variants in several SPD families and their etiological mechanism are still largely unknown.Methods: Whole exome and PCR-sanger sequencing followed by two-point linkage analysis were performed to identify the pathogenic variant in a six-generation Chinese pedigree. Homology modeling in combination with the RNAi and qRT-PCR experiments was used for revealing the pathogenic mechanism of the TTC30B variant.Results: A six-generation SPD family was reported. The affected subjects in this family had no other clinical malformation beyond SPD. A rare missense variant c.1157C > T [p.Ala375Val] (chr2:178416368, hg19) in TTC30B was demonstrated to be responsible for this SPD family. The modeling structure indicated that the Ala375 was evolutionarily and structurally conserved. The variant p.Ala375Val was predicted to be deleterious for protein structure and/or stability. Two-point linkage analysis resulted in a maximum LOD score of 3.1444 (P = 0.000071). Furthermore, we found that TTC30B was regulated by the Shh signaling pathway and the abnormal expression of TTC30B will affect the activation of the Shh signaling pathway in human retinal pigment epithelial cells.Conclusions: This study demonstrates for the first time that an IFT (intratlagellar transport) - related gene TTC30B is implicated with SPD.