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February 26, 2016PLoS GeneticsOpen Access

DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia

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Authors

YLYou LiHYHisato YagiEOEzenwa Obi Onuoha

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Overview

Functional genetic study reveals that DNAH6 mutations interact with primary ciliary dyskinesia genes to cause heterotaxy, indicating an oligogenic mechanism in human ciliopathies.

Key Points

  • To determine the role of DNAH6 mutations and their potential trans-heterozygous interactions with known primary ciliary dyskinesia genes in left-right patterning defects and ciliary dysfunction.
  • Analyzed exome sequencing data from 25 heterotaxy patients stratified by airway ciliary defects, followed by targeted sequencing in a cohort of 149 additional heterotaxy patients.
  • Conducted morpholino-mediated knockdown of dnah6 in zebrafish embryos to assess motile cilia in Kupffer's vesicle and internal organ looping.
  • Performed single and subthreshold dual knockdowns of DNAH6 with DNAI1 or DNAH5 in zebrafish and respiratory epithelial tissue from mutant mice.
  • dnah6 knockdown in zebrafish disrupted Kupffer's vesicle motile cilia and caused heterotaxy with abnormal cardiac and gut looping, matching defects observed after DNAH6 knockdown in human and mouse airway epithelia.
  • Five of six heterotaxy patients harboring heterozygous DNAH6 mutations also carried heterozygous mutations in DNAH5 or other primary ciliary dyskinesia genes.
  • Subthreshold double knockdown of DNAH6 with DNAH5 or DNAI1 provoked heterotaxy in zebrafish and disrupted ciliary motility in mouse respiratory epithelia, confirming synergistic trans-heterozygous effects.

Cite This Study

Li et al. (2016) studied this question.

synapsesocial.com/papers/6a94841761244928ec0100e5https://doi.org/10.1371/journal.pgen.1005821
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1DNAH10 mutation cause primary ciliary dyskinesia with defects of IDAf complex assembly and lung fibrosis manifestation2025
  2. 2Variants in the DNAH11 gene responsible for primary ciliary dyskinesia or probably atypical primary ciliary dyskinesia presenting left-right asymmetry disorder2026
  3. 3Primary ciliary dyskinesia: a case report of double DNAH11 mutant alleles2024 · 2 citations
  4. 4Functional Characterization of a Novel Homozygous DNAH5 Single-Nucleotide Intronic Deletion in a Consanguineous Portuguese Family with Primary Ciliary Dyskinesia2026
  5. 5Proteomic and structural comparison between cilia from primary ciliary dyskinesia patients with a DNAH5 defect2025 · 5 citations