CFAP300 mutation causing primary ciliary dyskinesia in Finland.
CFAP300 mutation causing primary ciliary dyskinesia in Finland.
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DOI：
10.3389/fgene.2022.985227
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发表时间：
2022
影响因子：
3.7
通讯作者：
Sironen, Anu I.
中科院分区：
文献类型：
--
作者：
Schultz, Ruediger;Elenius, Varpu;Fassad, Mahmoud R.;Freke, Grace;Rogers, Andrew;Shoemark, Amelia;Koistinen, Tiina;Mohamed, Mai A.;Lim, Jacqueline S. Y.;Mitchison, Hannah M.;Sironen, Anu I.
原发性纤毛运动障碍（PCD）是一种罕见的遗传性疾病，其特征是慢性呼吸道感染，在某些情况下，偏侧缺陷和不育。PCD的症状是由运动纤毛的功能障碍引起的，运动纤毛是从细胞中突出的毛状细胞器，其负责从气道中去除粘液并在胚胎发育期间组织内部器官定位。PCD是由编码运动纤毛中的结构或组装蛋白的基因突变引起的。到目前为止，已经确定了50多个基因的突变，这些变异解释了大约70%的已知病例。已经报道了PCD的群体特异性遗传学基础，从而突出了表征不同群体中的基因变异对于开发基于基因的诊断的重要性。在这项研究中，我们确定了一个经常性的功能丧失突变c.198_200delinsCC CFAP300导致缺乏的蛋白质产品。对于鉴定的CFAP 300突变纯合子的PCD患者具有不动的气道上皮纤毛，其纤毛轴丝中与动力蛋白臂缺失相关。此外，使用超分辨率显微镜，我们表明，CFAP 300运输沿着纤毛在正常人气道上皮细胞中，这表明CFAP 300的作用，除了在细胞质中的预组装的动力蛋白复合物运输。我们的研究结果强调了CFAP 300在动力蛋白臂组装中的重要性，并提高了芬兰PCD的诊断。
Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.
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影响因子：
9.8
作者：
Fassad, Mahmoud R.;Shoemark, Amelia;Mitchison, Hannah M.
通讯作者：
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影响因子：
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DOI：
10.1073/pnas.1715915115
发表时间：
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影响因子：
11.1
作者：
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通讯作者：
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影响因子：
30.8
作者：
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通讯作者：
Mitchell, David R.