title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
abstract: Multiciliated epithelial cells protect the upper and lower airways from chronic bacterial infections by moving mucus and debris outward. Congenital disorders of ciliary beating, referred to as primary ciliary dyskinesia (PCD), are characterized by deficient mucociliary clearance and severe, recurrent respiratory infections. Numerous genetic defects, most of which can be detected by transmission electron microscopy (TEM), are so far known to cause different abnormalities of the ciliary axoneme. However, some defects are not regularly discernable by TEM because the ciliary architecture of the axoneme remains preserved. This applies in particular to isolated defects of the nexin links, also known as the nexin-dynein regulatory complex (N-DRC), connecting the peripheral outer microtubular doublets. Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect. Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families.
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany. Electronic address: heike.olbrich@ukmuenster.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Cremers
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.affiliation: Danish PCD Centre, Pediatric Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Kim G
authors.initials: KG
authors.lastname: Nielsen
authors.affiliation: Danish PCD Centre, Pediatric Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: June K
authors.initials: JK
authors.lastname: Marthin
authors.affiliation: Danish PCD Centre, Pediatric Pulmonary Service, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Philipsen
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Wallmeier
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Menchen
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Edelbusch
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwartz
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Pulmonary Specialist Practice, 40217 Duesseldorf, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rommelmann
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany. Electronic address: heymut.omran@ukmuenster.de.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002648:Child; D002923:Cilia / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004398:Dyneins / Q000037:antagonists & inhibitors* / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007619:Kartagener Syndrome / Q000209:etiology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics*; D009569:Nitric Oxide / Q000032:analysis; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D058255:Protease Nexins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012137:Respiratory System; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C115742:GAS8 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D058255:Protease Nexins; D009569:Nitric Oxide; D004398:Dyneins