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          Institute: MPI für molekulare Genetik     Collection: Sequencing Group     Display Documents

ID: 413810.0, MPI für molekulare Genetik / Sequencing Group
DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm
Authors:Loges, Niki Tomas; Olbrich, Heike; Fenske, Lale; Mussaffi, Huda; Horvath, Judit; Fliegauf, Manfred; Kuhl, Heiner; Baktai, Gyorgy; Peterffy, Erzsebet; Chodhari, Rahul; Chung, Eddie M.K.; Rutman, Andrew; O'Callaghan, Christopher; Blau, Hannah; Tiszlavicz, Laszlo; Voelkel, Katarzyna; Witt, Michal; Ziętkiewicz, Ewa; Neesen, Juergen; Reinhardt, Richard; Mitchison, Hannah M.; Omran, Heymut
Date of Publication (YYYY-MM-DD):2008-10-23
Title of Journal:The American Journal of Human Genetics
Journal Abbrev.:Am J Hum Genet
Issue / Number:5
Start Page:547
End Page:558
Copyright:2008 The American Society of Human Genetics. All rights reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G > A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes.
External Publication Status:published
Document Type:Article
Communicated by:Richard Reinhardt
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany;
2.Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany;
3.Pulmonary Unit, Schneider Children's Medical Center of Israel, Petah-Tikva, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
4.National Medical Center, Budapest, Hungaria;
5.Pediatric Institute Svabhegy, Budapest, Hungary;
6.General and Adolescent Paediatric Unit, University College London, Institute of Child Health, London, UK;
7.Department of Infection, Immunity and Inflammation, Division of Child Health, University of Leicester, Leicester Royal Infirmary, Leicester, UK;
8.University of Szeged, Department of Pathology, Szeged, Hungary;
9.Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland;
10.International Institute of Molecular and Cell Biology, Warsaw, Poland;
11.Department of Medical Genetics, University of Vienna, Vienna, Austria.
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