Bakey Zeineb, Cabrera Oscar A, Hoefele Julia, Antony Dinu, Wu Kaman, Stuck Michael W, Micha Dimitra, Eguether Thibaut, Smith Abigail O, van der Wel Nicole N, Wagner Matias, Strittmatter Lara, Beales Philip L, Jonassen Julie A, Thiffault Isabelle, Cadieux-Dion Maxime, Boyes Laura, Sharif Saba, Tüysüz Beyhan, Dunstheimer Desiree, Niessen Hans W M, Devine William, Lo Cecilia W, Mitchison Hannah M, Schmidts Miriam, Pazour Gregory J
medRxiv. 2023 Feb 26:2023.02.23.23286106. doi: 10.1101/2023.02.23.23286106.
Motile and non-motile cilia are critical to mammalian development and health. Assembly of these organelles depends on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). A series of human and mouse variants were studied to understand the function of this IFT subunit. Humans missing exon 2, which codes for the first 40 residues, presented an unusual combination of ciliary chondrodysplasia and mucociliary clearance disorders while individuals carrying biallelic splice site variants developed a lethal skeletal chondrodysplasia. In mice, variants thought to remove all Ift74 function, completely block ciliary assembly and result in midgestational lethality. A mouse allele that removes the first 40 amino acids, analogous to the human exon 2 deletion, results in a motile cilia phenotype with mild skeletal abnormalities. studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia could account for the motile cilia phenotype observed in human and mice.
运动性纤毛和非运动性纤毛对哺乳动物的发育和健康至关重要。这些细胞器的组装依赖于在细胞体中合成并通过鞭毛内运输（IFT）转运到纤毛中的蛋白质。研究了一系列人类和小鼠变体，以了解这种IFT亚基的功能。缺失编码前40个残基的外显子2的人类表现出纤毛软骨发育不良和黏液纤毛清除障碍的异常组合，而携带双等位基因剪接位点变体的个体则发展为致命的骨骼软骨发育不良。在小鼠中，被认为消除所有Ift74功能的变体完全阻断纤毛组装并导致妊娠中期致死。一个去除前40个氨基酸的小鼠等位基因，类似于人类外显子2缺失，导致具有轻度骨骼异常的运动性纤毛表型。研究表明，IFT74的前40个氨基酸对于与其他IFT亚基的结合是可有可无的，但对于微管蛋白结合很重要。与初级纤毛相比，运动性纤毛对微管蛋白运输的更高需求可能解释了在人类和小鼠中观察到的运动性纤毛表型。
