Miriam Schmidts, theme Renal disorders, and colleagues, discovered that recessive DNAH9 loss-of-function mutations cause laterality defects and subtle respiratory ciliary-beating defects. Their exciting findings are published in the American Journal of Human Genetics.Publication: Link.
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 γ-HC DNAH5, proximally located β-HC DNAH11 (defining ODA type 1), and the distally localized β-HC DNAH9 (defining ODA type 2). Here they 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. They further showed that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme.They proposed that the β-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient β-HCs such as that of the unicellular Chlamydomonas reinhardtii.
Related news items
H2020 Grant for Frank Walboomers and Ronald Bartels23 May 2019
Frank Walboomers and Ronald Bartels, theme Reconstructive and regenerative medicine, have received a € 500,000 grant for research into graphene biomaterials from the Europan Union Horizon 2020 FET Open programme.read more
Innovation Grant Dutch Kidney Foundation for Jeroen de Baaij23 May 2019
Jeroen de Baaij, theme Renal disorders, was awarded with an Innovation Grant of the Dutch Kidney Foundation. Jeroen's research proposal was selected from a competitive field of innovative approaches to treat kidney disease.read more
Graduate school news Adjusted PhD guidelines23 May 2019
It should be emphasized that the quality, and not the number of chapters, determines the assessment by the manuscript committee. To avoid the wrong emphasis on quantity, it is not recommended to have more than three publishable chapters in the thesis.read more
Stress among PhD candidates23 May 2019
Do you struggle with too much stress at work or with your PhD project and is there a high workload? Are there problems with your supervisor or a colleague that you cannot resolve? Do you miss a balance between work and private life? Then make an appointment with one of our Radboudumc counselors.read more
Secure trial usual care to a restrictive patient selection for gallbladder surgery23 May 2019
In Lancet Kees van Laarhoven and colleagues showed that usual care for gallstone patients is suboptimal and that less than two third of patients are pain-free after surgery.read more