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

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

doi:10.1016/j.gim.2022.07.019

Cited by 5 publications

(4 citation statements)

References 43 publications

(65 reference statements)

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“…Besides Arl13b and Arl3, IFT complex, Hydin and the ODA complex are confirmed human ciliopathy genes (1). Recent analyses of ODA16 homologs in mice and humans also demonstrate a link of this gene to primary ciliary dyskinesia, congenital heart diseases and other motile ciliopathies (33,49,50). The current study thus also shed light on the disease mechanisms of these genes.…”

Section: Discussionsupporting

confidence: 53%

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Arl3 regulates ODA16-mediated intraflagellar transport in motile cilia biogenesis

Huang

Dong

Sun

et al. 2023

Preprint

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Arl13b and Arl3 are ciliary GTPases implicated in human Joubert Syndrome, affecting ciliary membrane and axoneme organization. Although the mechanism of Arl13b as a guanine nucleotide exchange factor (GEF) of Arl3 and the function of Arl13b and Arl3 in ciliary membrane protein transport are well established, their role in axoneme biogenesis is unclear. InTrypanosoma brucei, TbArl13 acts as a GEF for two distinct TbArl3 proteins, TbArl3A and TbArl3C. Here, we identified theT. bruceihomolog of ODA16, a cargo adapter facilitating intraflagellar transport (IFT) of motile ciliary components, as an effector of both TbArl3A and TbArl3C. Depletion of TbArl3 GTPases stabilized TbODA16 interaction with IFT, while active TbArl3 variants displaced TbODA16 from IFT, demonstrating a mechanism of TbArl3 in motile ciliary cargo transport.

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Section: Discussionsupporting

confidence: 53%

“…2F). Similarly in C. reinhardtii, zebrafish and human, ODA16 facilitates efficient ODA trafficking, but ODA16 deficiency does not completely inhibit ODA import into the cilia (24,32,33). Other cargo adapters, for example ODA8 (34), may also facilitate flagellar transport of ODA complexes.…”

Section: Tboda16 Is Required For Axonemal Assemblymentioning

confidence: 99%

Arl3 regulates ODA16-mediated intraflagellar transport in motile cilia biogenesis

Huang

Dong

Sun

et al. 2023

Preprint

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“…To date, around 30% of PCD cases remain genetically unsolved [ 25 ], and mild PCD cases are significantly underdiagnosed. Lately, several genes have been reported to be associated with laterality defects, male infertility, and mild variable respiratory phenotypes such as CCDC11/CFAP53 , ENKUR , WDR16/CFAP52 , DAW1 , and MNS1 [ 15 , 16 , 17 , 18 , 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…While most of these genes are primarily associated with respiratory symptoms, recently, a small subset of these genes have been described in association with laterality defects and male infertility but with mild or no respiratory symptoms. Notable among these are pathogenic variants in genes such as CCDC11/CFAP53 , ENKUR , WDR16/CFAP52 , DAW1 , and MNS1 [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. These discoveries highlight the diverse impact of ciliary dysfunction beyond respiratory disease, emphasizing the importance of cilia in body asymmetry and reproductive health.…”

Section: Introductionmentioning

confidence: 99%

Biallelic Variants in MNS1 Are Associated with Laterality Defects and Respiratory Involvement

Hjeij,

Leslie,

Rizk

et al. 2024

Cells

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Defects in motile cilia, termed motile ciliopathies, result in clinical manifestations affecting the respiratory and reproductive system, as well as laterality defects and hydrocephalus. We previously defined biallelic MNS1 variants causing situs inversus and male infertility, mirroring the findings in Mns1−/− mice. Here, we present clinical and genomic findings in five newly identified individuals from four unrelated families affected by MNS1-related disorder. Ciliopathy panel testing and whole exome sequencing identified one previously reported and two novel MNS1 variants extending the genotypic spectrum of disease. A broad spectrum of laterality defects including situs inversus totalis and heterotaxia was confirmed. Interestingly, a single affected six-year-old girl homozygous for an MNS1 nonsense variant presented with a history of neonatal respiratory distress syndrome, recurrent respiratory tract infections, chronic rhinitis, and wet cough. Accordingly, immunofluorescence analysis showed the absence of MNS1 from the respiratory epithelial cells of this individual. Two other individuals with hypomorphic variants showed laterality defects and mild respiratory phenotype. This study represents the first observation of heterotaxia and respiratory disease in individuals with biallelic MNS1 variants, an important extension of the phenotype associated with MNS1-related motile ciliopathy disorder.

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Primary ciliary dyskinesia

Pennekamp¹,

Raidt²,

Wohlgemuth³

et al. 2023

Rare Diseases of the Respiratory System

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

Cited by 5 publications

References 43 publications

Arl3 regulates ODA16-mediated intraflagellar transport in motile cilia biogenesis

Arl3 regulates ODA16-mediated intraflagellar transport in motile cilia biogenesis

Biallelic Variants in MNS1 Are Associated with Laterality Defects and Respiratory Involvement

Primary ciliary dyskinesia

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