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Am J Hum Genet. 2018 Dec 6;103(6):995-1008. doi: 10.1016/j.ajhg.2018.10.020. Epub 2018 Nov 21.

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

Author information

1
Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany.
2
Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL Nijmegen, the Netherlands; Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Mathildenstrasse 1, 79112 Freiburg, Germany.
3
Clinical Institute of Medical Genetics, UMC Ljubljana, Šlajmerjeva 4, 1000 Ljubljana, Slovenia.
4
Departments of Pediatrics and Pathology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Laboratory Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Medical Genetics, University of Health Sciences, Kanuni Sultan Suleyman Training and Research Hospital, 34303 Istanbul, Turkey.
6
Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL Nijmegen, the Netherlands.
7
Departments of Pediatrics and Pathology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
8
Department of Medical Genetics, University Children's Hospital, 11000 Belgrade, Serbia.
9
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
10
Laboratory Medicine, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
11
University of Health Sciences, Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, Department of Pediatric Cardiology, 34303 Istanbul, Turkey.
12
Department of General Pediatrics, University Hospital Muenster, 48149 Muenster, Germany. Electronic address: heymut.omran@ukmuenster.de.
13
Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL Nijmegen, the Netherlands; Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Mathildenstrasse 1, 79112 Freiburg, Germany. Electronic address: miriam.schmidts@uniklinik-freiburg.de.

Abstract

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 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 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.

KEYWORDS:

DNAH11; DNAH9; PCD; outer dynein arm; primary ciliary dyskinesia; situs inversus

PMID:
30471718
PMCID:
PMC6288205
[Available on 2019-06-06]
DOI:
10.1016/j.ajhg.2018.10.020
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