CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability

Congenital heart disease (CHD) is the most common and lethal birth defect, affecting 1.3 million individuals worldwide. During early embryogenesis, errors in Left-Right (LR) patterning called Heterotaxy (Htx) can lead to severe CHD. Many of the genetic underpinnings of Htx/CHD remain unknown. In ana...

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Published in:	Developmental biology Vol. 499; pp. 75 - 88
Main Authors:	Deniz, E., Pasha, M., Guerra, M.E., Viviano, S., Ji, W., Konstantino, M., Jeffries, L., Lakhani, S.A., Medne, L., Skraban, C., Krantz, I., Khokha, M.K.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2023
Subjects:	Animals Body Patterning - genetics CFAP45 Cilia Cilia - genetics Cilia - metabolism Congenital heart disease Heart Defects, Congenital - genetics Heart Defects, Congenital - metabolism Heterotaxy Heterotaxy Syndrome - genetics Mutation, Missense Phenotype Xenopus Xenopus - abnormalities Xenopus Proteins - metabolism Xenopus Heterotaxy Congenital heart disease CFAP45 Cilia
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Summary:	Congenital heart disease (CHD) is the most common and lethal birth defect, affecting 1.3 million individuals worldwide. During early embryogenesis, errors in Left-Right (LR) patterning called Heterotaxy (Htx) can lead to severe CHD. Many of the genetic underpinnings of Htx/CHD remain unknown. In analyzing a family with Htx/CHD using whole-exome sequencing, we identified a homozygous recessive missense mutation in CFAP45 in two affected siblings. CFAP45 belongs to the coiled-coil domain-containing protein family, and its role in development is emerging. When we depleted Cfap45 in frog embryos, we detected abnormalities in cardiac looping and global markers of LR patterning, recapitulating the patient's heterotaxy phenotype. In vertebrates, laterality is broken at the Left-Right Organizer (LRO) by motile monocilia that generate leftward fluid flow. When we analyzed the LRO in embryos depleted of Cfap45, we discovered “bulges” within the cilia of these monociliated cells. In addition, epidermal multiciliated cells lost cilia with Cfap45 depletion. Via live confocal imaging, we found that Cfap45 localizes in a punctate but static position within the ciliary axoneme, and depletion leads to loss of cilia stability and eventual detachment from the cell's apical surface. This work demonstrates that in Xenopus, Cfap45 is required to sustain cilia stability in multiciliated and monociliated cells, providing a plausible mechanism for its role in heterotaxy and congenital heart disease. [Display omitted] •Underlying genetic defects in congenital heart diseases (CHDs) are mostly unknown.•Homozygous mutation in CFAP45 was identified in two patients presenting with CHDs.•CFAP45 loss-of-function in Xenopus leads to heterotaxy.•CFAP45 is required for cilia stability in mono and multiciliated cells, suggesting its role in CHDs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0012-1606 1095-564X
DOI:	10.1016/j.ydbio.2023.04.006