Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects

Niki T. Loges, Dinu Antony, Ales Maver, Matthew A. Deardorff, Elif Yylmaz Gulec, Alper Gezdirici, Tabea Noethe-Menchen, Inga M. Hoeben, Lena Jelten, Diana Frank, Claudius Werner, Johannes Tebbe, Kaman Wu, Elizabeth Goldmuntz, Goran Cuturilo, Bryan Krock, Alyssa Ritter, Rim Hjeij, Zeineb Bakey, Petra PennekampBernd Dworniczak, Han Brunner, Borut Peterlin, Cansaran Tanidir, Heike Olbrich, Heymut Omran*, Miriam Schmidts*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

72 Citations (Web of Science)


Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed gamma-HC DNAH5, proximally located beta-HC DNAH11 (defining ODA type 1), and the distally localized beta-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co-immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the beta-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient beta-HCs such as that of the unicellular Chlamydomonas reinhardtii.

Original languageEnglish
Pages (from-to)995-1008
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 6 Dec 2018



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