Dataset Information

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

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.

SUBMITTER: Hjeij R

PROVIDER: S-EPMC3738828 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Hjeij Rim R Lindstrand Anna A Francis Richard R Zariwala Maimoona A MA Liu Xiaoqin X Li You Y Damerla Rama R Dougherty Gerard W GW Abouhamed Marouan M Olbrich Heike H Loges Niki T NT Pennekamp Petra P Davis Erica E EE Carvalho Claudia M B CM Pehlivan Davut D Werner Claudius C Raidt Johanna J Köhler Gabriele G Häffner Karsten K Reyes-Mugica Miguel M Lupski James R JR Leigh Margaret W MW Rosenfeld Margaret M Morgan Lucy C LC Knowles Michael R MR Lo Cecilia W CW Katsanis Nicholas N Omran Heymut H

American journal of human genetics 20130711 2

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 mu ...[more]

PMID: 23849778

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Project description:Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left-right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307(∗)), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus.

Dataset Information

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

Publications

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

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