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

You Li, Hisato Yagi, Ezenwa Obi Onuoha, Rama Rao Damerla, Richard Francis, Yoshiyuki Furutani, Muhammad Tariq, Stephen M. King, Gregory Hendricks, Cheng Cui, Manush Saydmohammed, Dong Min Lee, Maliha Zahid, Iman Sami, Linda Leatherbury, Gregory J. Pazour, Stephanie Ware, Toshio Nakanishi, Elizabeth Goldmuntz, Michael TsangCecilia W. Lo

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Heterotaxy, a birth defect involving left-right patterning defects, and primary ciliary dyskinesia (PCD), a sinopulmonary disease with dyskinetic/immotile cilia in the airway are seemingly disparate diseases. However, they have an overlapping genetic etiology involving mutations in cilia genes, a reflection of the common requirement for motile cilia in left-right patterning and airway clearance. While PCD is a monogenic recessive disorder, heterotaxy has a more complex, largely non-monogenic etiology. In this study, we show mutations in the novel dynein gene DNAH6 can cause heterotaxy and ciliary dysfunction similar to PCD. We provide the first evidence that trans-heterozygous interactions between DNAH6 and other PCD genes potentially can cause heterotaxy. DNAH6 was initially identified as a candidate heterotaxy/PCD gene by filtering exome-sequencing data from 25 heterotaxy patients stratified by whether they have airway motile cilia defects. dnah6 morpholino knockdown in zebrafish disrupted motile cilia in Kupffer’s vesicle required for left-right patterning and caused heterotaxy with abnormal cardiac/gut looping. Similarly DNAH6 shRNA knockdown disrupted motile cilia in human and mouse respiratory epithelia. Notably a heterotaxy patient harboring heterozygous DNAH6 mutation was identified to also carry a rare heterozygous PCD-causing DNAI1 mutation, suggesting a DNAH6/DNAI1 trans-heterozygous interaction. Furthermore, sequencing of 149 additional heterotaxy patients showed 5 of 6 patients with heterozygous DNAH6 mutations also had heterozygous mutations in DNAH5 or other PCD genes. We functionally assayed for DNAH6/DNAH5 and DNAH6/DNAI1 trans-heterozygous interactions using subthreshold double-morpholino knockdown in zebrafish and showed this caused heterotaxy. Similarly, subthreshold siRNA knockdown of Dnah6 in heterozygous Dnah5 or Dnai1 mutant mouse respiratory epithelia disrupted motile cilia function. Together, these findings support an oligogenic disease model with broad relevance for further interrogating the genetic etiology of human ciliopathies.

Original languageEnglish (US)
Article numbere1005821
JournalPLoS Genetics
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

dyskinesia
Kartagener Syndrome
Cilia
cilia
mutation
gene
etiology
Mutation
Genes
defect
genes
respiratory mucosa
Morpholinos
Respiratory Mucosa
Zebrafish
Danio rerio
Small Interfering RNA
Exome
Dyneins
vesicle

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Li, Y., Yagi, H., Onuoha, E. O., Damerla, R. R., Francis, R., Furutani, Y., ... Lo, C. W. (2016). DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. PLoS Genetics, 12(2), [e1005821]. https://doi.org/10.1371/journal.pgen.1005821

DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. / Li, You; Yagi, Hisato; Onuoha, Ezenwa Obi; Damerla, Rama Rao; Francis, Richard; Furutani, Yoshiyuki; Tariq, Muhammad; King, Stephen M.; Hendricks, Gregory; Cui, Cheng; Saydmohammed, Manush; Lee, Dong Min; Zahid, Maliha; Sami, Iman; Leatherbury, Linda; Pazour, Gregory J.; Ware, Stephanie; Nakanishi, Toshio; Goldmuntz, Elizabeth; Tsang, Michael; Lo, Cecilia W.

In: PLoS Genetics, Vol. 12, No. 2, e1005821, 01.02.2016.

Research output: Contribution to journalArticle

Li, Y, Yagi, H, Onuoha, EO, Damerla, RR, Francis, R, Furutani, Y, Tariq, M, King, SM, Hendricks, G, Cui, C, Saydmohammed, M, Lee, DM, Zahid, M, Sami, I, Leatherbury, L, Pazour, GJ, Ware, S, Nakanishi, T, Goldmuntz, E, Tsang, M & Lo, CW 2016, 'DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia', PLoS Genetics, vol. 12, no. 2, e1005821. https://doi.org/10.1371/journal.pgen.1005821
Li Y, Yagi H, Onuoha EO, Damerla RR, Francis R, Furutani Y et al. DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. PLoS Genetics. 2016 Feb 1;12(2). e1005821. https://doi.org/10.1371/journal.pgen.1005821
Li, You ; Yagi, Hisato ; Onuoha, Ezenwa Obi ; Damerla, Rama Rao ; Francis, Richard ; Furutani, Yoshiyuki ; Tariq, Muhammad ; King, Stephen M. ; Hendricks, Gregory ; Cui, Cheng ; Saydmohammed, Manush ; Lee, Dong Min ; Zahid, Maliha ; Sami, Iman ; Leatherbury, Linda ; Pazour, Gregory J. ; Ware, Stephanie ; Nakanishi, Toshio ; Goldmuntz, Elizabeth ; Tsang, Michael ; Lo, Cecilia W. / DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. In: PLoS Genetics. 2016 ; Vol. 12, No. 2.
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AU - Francis, Richard

AU - Furutani, Yoshiyuki

AU - Tariq, Muhammad

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AU - Leatherbury, Linda

AU - Pazour, Gregory J.

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