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: Heike Olbrich, Carolin Cremers, Niki T Loges, Claudius Werner, Kim G Nielsen, June K Marthin, Maria Philipsen, Julia Wallmeier, Petra Pennekamp, Tabea Menchen, Christine Edelbusch, Gerard W Dougherty, Oliver Schwartz, Holger Thiele, Janine Altmüller, Frank Rommelmann, Heymut Omran
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 97 Issue 4 Pg. 546-54 (Oct 01 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 26387594 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytoskeletal Proteins
• GAS8 protein, human
• Intracellular Signaling Peptides and Proteins
• Lnk protein, mouse
• Membrane Proteins
• Multiprotein Complexes
• Neoplasm Proteins
• Protease Nexins
• Nitric Oxide
• Dyneins

Topics

• Adaptor Proteins, Signal Transducing
• Adult
• Animals
• Blotting, Western
• Child
• Cilia (physiology)
• Cytoskeletal Proteins (genetics)
• Dyneins (antagonists & inhibitors, genetics)
• Exome (genetics)
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (physiology)
• Kartagener Syndrome (etiology, pathology)
• Male
• Membrane Proteins
• Mice
• Mice, Knockout
• Microscopy, Electron, Transmission
• Microscopy, Fluorescence
• Multiprotein Complexes (antagonists & inhibitors, genetics)
• Mutation (genetics)
• Nasal Mucosa (cytology, metabolism)
• Neoplasm Proteins (genetics)
• Nitric Oxide (analysis)
• Pedigree
• Phenotype
• Prognosis
• Protease Nexins (antagonists & inhibitors, genetics)
• Respiratory System
• Young Adult