Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

Joseph S. Leslie; Rim Hjeij; Asaf Vivante; Elizabeth A. Bearce; Laura Dyer; Jiaolong Wang; Lettie Rawlins; Joanna Kennedy; Nishanka Ubeyratna; James Fasham; Zoe H. Irons; Samuel B. Craig; Julia Koenig; Sebastian George; Ben Pode-Shakked; Yoav Bolkier; Ortal Barel; Shrikant Mane; Kathrine K. Frederiksen; Olivia Wenger; Ethan Scott; Harold E. Cross; Esben Lorentzen; Dominic P. Norris; Yair Anikster; Heymut Omran; Daniel T. Grimes; Andrew H. Crosby; Emma L. Baple

doi:10.1016/j.gim.2022.07.019

Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

Joseph S. Leslie, Rim Hjeij, Asaf Vivante, Elizabeth A. Bearce, Laura Dyer, Jiaolong Wang, Lettie Rawlins, Joanna Kennedy, Nishanka Ubeyratna, James Fasham, Zoe H. Irons, Samuel B. Craig, Julia Koenig, Sebastian George, Ben Pode-Shakked, Yoav Bolkier, Ortal Barel, Shrikant Mane, Kathrine K. Frederiksen, Olivia WengerEthan Scott, Harold E. Cross, Esben Lorentzen, Dominic P. Norris, Yair Anikster, Heymut Omran, Daniel T. Grimes, Andrew H. Crosby, Emma L. Baple^*

^*Corresponding author for this work

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Abstract

Purpose: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. Methods: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. Results: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. Conclusion: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.

Original language	English
Journal	Genetics in Medicine
Volume	24
Issue	11
Pages (from-to)	2249-2261
ISSN	1098-3600
DOIs	https://doi.org/10.1016/j.gim.2022.07.019
Publication status	Published - Nov 2022

Keywords

DAW1
Heterotaxy
Left-right asymmetry
Motile cilia
Primary ciliary dyskinesia

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1-s2.0-S109836002200870X-mainFinal published version, 2.13 MBLicence: CC BY

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Leslie, J. S., Hjeij, R., Vivante, A., Bearce, E. A., Dyer, L., Wang, J., Rawlins, L., Kennedy, J., Ubeyratna, N., Fasham, J., Irons, Z. H., Craig, S. B., Koenig, J., George, S., Pode-Shakked, B., Bolkier, Y., Barel, O., Mane, S., Frederiksen, K. K., ... Baple, E. L. (2022). Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities. Genetics in Medicine, 24(11), 2249-2261. https://doi.org/10.1016/j.gim.2022.07.019

@article{7b4a9a5f60ea4e3a8fe56f943101cb02,

title = "Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities",

abstract = "Purpose: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. Methods: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. Results: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. Conclusion: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.",

keywords = "DAW1, Heterotaxy, Left-right asymmetry, Motile cilia, Primary ciliary dyskinesia",

author = "Leslie, {Joseph S.} and Rim Hjeij and Asaf Vivante and Bearce, {Elizabeth A.} and Laura Dyer and Jiaolong Wang and Lettie Rawlins and Joanna Kennedy and Nishanka Ubeyratna and James Fasham and Irons, {Zoe H.} and Craig, {Samuel B.} and Julia Koenig and Sebastian George and Ben Pode-Shakked and Yoav Bolkier and Ortal Barel and Shrikant Mane and Frederiksen, {Kathrine K.} and Olivia Wenger and Ethan Scott and Cross, {Harold E.} and Esben Lorentzen and Norris, {Dominic P.} and Yair Anikster and Heymut Omran and Grimes, {Daniel T.} and Crosby, {Andrew H.} and Baple, {Emma L.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

doi = "10.1016/j.gim.2022.07.019",

language = "English",

volume = "24",

pages = "2249--2261",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "11",

}

Leslie, JS, Hjeij, R, Vivante, A, Bearce, EA, Dyer, L, Wang, J, Rawlins, L, Kennedy, J, Ubeyratna, N, Fasham, J, Irons, ZH, Craig, SB, Koenig, J, George, S, Pode-Shakked, B, Bolkier, Y, Barel, O, Mane, S, Frederiksen, KK, Wenger, O, Scott, E, Cross, HE, Lorentzen, E, Norris, DP, Anikster, Y, Omran, H, Grimes, DT, Crosby, AH & Baple, EL 2022, 'Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities', Genetics in Medicine, vol. 24, no. 11, pp. 2249-2261. https://doi.org/10.1016/j.gim.2022.07.019

Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities. / Leslie, Joseph S.; Hjeij, Rim; Vivante, Asaf et al.
In: Genetics in Medicine, Vol. 24, No. 11, 11.2022, p. 2249-2261.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

AU - Leslie, Joseph S.

AU - Hjeij, Rim

AU - Vivante, Asaf

AU - Bearce, Elizabeth A.

AU - Dyer, Laura

AU - Wang, Jiaolong

AU - Rawlins, Lettie

AU - Kennedy, Joanna

AU - Ubeyratna, Nishanka

AU - Fasham, James

AU - Irons, Zoe H.

AU - Craig, Samuel B.

AU - Koenig, Julia

AU - George, Sebastian

AU - Pode-Shakked, Ben

AU - Bolkier, Yoav

AU - Barel, Ortal

AU - Mane, Shrikant

AU - Frederiksen, Kathrine K.

AU - Wenger, Olivia

AU - Scott, Ethan

AU - Cross, Harold E.

AU - Lorentzen, Esben

AU - Norris, Dominic P.

AU - Anikster, Yair

AU - Omran, Heymut

AU - Grimes, Daniel T.

AU - Crosby, Andrew H.

AU - Baple, Emma L.

PY - 2022/11

Y1 - 2022/11

N2 - Purpose: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. Methods: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. Results: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. Conclusion: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.

AB - Purpose: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. Methods: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. Results: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. Conclusion: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.

KW - DAW1

KW - Heterotaxy

KW - Left-right asymmetry

KW - Motile cilia

KW - Primary ciliary dyskinesia

U2 - 10.1016/j.gim.2022.07.019

DO - 10.1016/j.gim.2022.07.019

M3 - Journal article

C2 - 36074124

AN - SCOPUS:85137606845

SN - 1098-3600

VL - 24

SP - 2249

EP - 2261

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

ER -

Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities

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Keywords

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