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 M., Nakanishi, Toshio, Goldmuntz, Elizabeth, Tsang, Michael, and Lo, Cecilia W. (2016) DNAH6 and its interactions with PCD genes in heterotaxy and primary ciliary dyskinesia. PLoS Genetics, 12 (2). e1005821.

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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.

Item ID: 60721
Item Type: Article (Research - C1)
ISSN: 1553-7404
Copyright Information: © 2016 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funders: Pennsylvania Department of Health, National Institute of Health (NIH), USA
Projects and Grants: NIH HL098180, NIH GM104412, NIH GM060992, NIH HL062177, NIH HL074731, NIH NCRRUL1RR024134
Date Deposited: 23 Oct 2019 12:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 40%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 40%
06 BIOLOGICAL SCIENCES > 0606 Physiology > 060602 Animal Physiology - Cell @ 20%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 40%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920115 Respiratory System and Diseases (incl. Asthma) @ 20%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920110 Inherited Diseases (incl. Gene Therapy) @ 40%
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