ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.

TitleARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.
Publication TypeJournal Article
Year of Publication2013
AuthorsHjeij, R, Lindstrand, A, Francis, R, Zariwala, MA, Liu, X, Li, Y, Damerla, R, Dougherty, GW, Abouhamed, M, Olbrich, H, Loges, NT, Pennekamp, P, Davis, EE, Carvalho, CMB, Pehlivan, D, Werner, C, Raidt, J, Köhler, G, Häffner, K, Reyes-Mugica, M, Lupski, JR, Leigh, MW, Rosenfeld, M, Morgan, LC, Knowles, MR, Lo, CW, Katsanis, N, Omran, H
JournalAm J Hum Genet
Volume93
Issue2
Pagination357-67
Date Published2013 Aug 8
ISSN1537-6605
KeywordsAmino Acid Sequence, Animals, Armadillo Domain Proteins, Axoneme, Body Patterning, Cilia, DNA Copy Number Variations, DNA Mutational Analysis, Dyneins, Gene Expression Regulation, Humans, Kartagener Syndrome, Mice, Microtubule-Associated Proteins, Molecular Sequence Data, Mutation, Respiratory System, Zebrafish
Abstract

The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.

DOI10.1016/j.ajhg.2013.06.009
Alternate JournalAm. J. Hum. Genet.
PubMed ID23849778
PubMed Central IDPMC3738828
Grant List5R0/NS058529 / NS / NINDS NIH HHS / United States
5U54HG006542 / HG / NHGRI NIH HHS / United States
DK072301 / DK / NIDDK NIH HHS / United States
R01 DK072301 / DK / NIDDK NIH HHS / United States
R01 HL071798 / HL / NHLBI NIH HHS / United States
R01 HL071798 / HL / NHLBI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
U01-HL098180 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54 HL096458-10 / HL / NHLBI NIH HHS / United States
U54 RR019480 / RR / NCRR NIH HHS / United States