Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome
Disrupted intraflagellar transport due to IFT74 variants causes Joubert syndrome
复制标题
IFT74 变异导致鞭毛内运输中断，导致 Joubert 综合征。
DOI：
10.1038/s41436-021-01106-z
复制
发表时间：
2021-02-02
影响因子：
8.8
通讯作者：
Cao, Muqing
中科院分区：
文献类型：
--
作者：
Luo, Minna;Lin, Zaisheng;Cao, Muqing
目的纤毛病是一组由纤毛缺陷引起的疾病。Joubert综合征（JBTS）是一种隐性和多效性纤毛病变，引起小脑蚓部发育不全和精神发育迟缓。虽然鞭毛内转运（IFT）复合物作为维持纤毛结构和调节纤毛信号传导的关键模块，但IFT在JBTS中的功能仍然很大程度上未知。我们的目的是探讨IFT功能障碍对JBTS的影响。方法采用外显子组测序技术对JBTS队列中IFT基因的致病性变异进行筛查。使用动物模型和患者来源的成纤维细胞来评估变体的致病作用。结果我们在3个无关家系中鉴定出一个JBTS相关基因。所有受影响的个体都携带截短的变异体，并共享一个仅在东亚人中发现的错义变异体（p.Q179E）。人p. Q179 E-IFFT 74变体的表达在斑马鱼ift 74变体中显示出受损的拯救作用。纤毛发生减弱;在具有IFT 74变体的患者成纤维细胞中观察到IFT蛋白和睫状膜蛋白（包括ARL 13 B、INPP 5E和GPR 161）的分布改变;以及hedgehog信号传导被破坏。结论IFT 74基因为JBTS相关基因。还提供了细胞和生物化学机制。
Purpose Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. Methods Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. Results We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. Conclusion IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.