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

Li, Y and Yagi, H and Onuoha, EO and Damerla, RR and Francis, R and Furutani, Y and Tariq, M and King, SM and Hendricks, G and Cui, C and Saydmohammed, M and Lee, DM and Zahid, M and Sami, I and Leatherbury, L and Pazour, GJ and Ware, SM and Nakanishi, T and Goldmuntz, E and Tsang, M and Lo, CW (2016) DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia. PLoS Genetics, 12 (2). ISSN 1553-7390

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Li, Y
Yagi, Hhisato@pitt.eduHISATO
Onuoha, EO
Damerla, RR
Francis, Rrfrancis@pitt.eduRFRANCIS
Furutani, Y
Tariq, M
King, SM
Hendricks, G
Cui, Cccui@pitt.eduCCUI
Saydmohammed, M
Lee, DM
Zahid, Mmaz7@pitt.eduMAZ7
Sami, I
Leatherbury, L
Pazour, GJ
Ware, SM
Nakanishi, T
Goldmuntz, E
Tsang, Mtsang@pitt.eduTSANG
Lo, CWcel36@pitt.eduCEL36
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 February 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Genetics
Volume: 12
Number: 2
DOI or Unique Handle: 10.1371/journal.pgen.1005821
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Developmental Biology
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 23 Aug 2016 13:41
Last Modified: 30 Mar 2021 13:56


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