Paff Tamara, Loges Niki T, Aprea Isabella, Wu Kaman, Bakey Zeineb, Haarman Eric G, Daniels Johannes M A, Sistermans Erik A, Bogunovic Natalija, Dougherty Gerard W, Höben Inga M, Große-Onnebrink Jörg, Matter Anja, Olbrich Heike, Werner Claudius, Pals Gerard, Schmidts Miriam, Omran Heymut, Micha Dimitra
Department of Pulmonary Diseases, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Paediatric Pulmonology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
Am J Hum Genet. 2017 Jan 5;100(1):160-168. doi: 10.1016/j.ajhg.2016.11.019. Epub 2016 Dec 29.
Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa.
运动性纤毛和精子鞭毛的缺陷会导致原发性纤毛运动障碍（PCD），其特征为慢性气道疾病、不育症以及左右体轴紊乱。在此，我们报告了4名患有PCD的男性中PIH1D3的母系遗传突变和新发突变。PIH1D3位于X染色体上，参与纤毛和精子鞭毛的外动力蛋白臂（ODA）和内动力蛋白臂（IDA）的预组装。PIH1D3的功能丧失突变会导致ODA缺失，IDA减少或缺失，从而导致纤毛和鞭毛运动障碍。此外，PIH1D3与细胞质ODA/IDA组装因子DNAAF2和DNAAF4相互作用并共沉淀。这一结果对于具有典型PCD表型但缺乏诸如智力残疾或色素性视网膜炎等其他表型的未解决遗传问题的男性病例具有临床和遗传咨询意义。
