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Dev Biol 2023 Jul 01;499:75-88. doi: 10.1016/j.ydbio.2023.04.006.
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CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability.

Deniz E , Pasha M , Guerra ME , Viviano S , Ji W , Konstantino M , Jeffries L , Lakhani SA , Medne L , Skraban C , Krantz I , Khokha MK .

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.

PubMed ID: 37172641
PMC ID: PMC10373286
Article link: Dev Biol
Grant support: [+]

Species referenced: Xenopus tropicalis
Genes referenced: arl13b cfap45 dand5 ift80 mcc pitx2
Antibodies: Arl13b Ab4 Ccdc19 Ab1 Phalloidin Ab3 Tuba4b Ab5
Morpholinos: cfap45 MO1
gRNAs referenced: cfap45 gRNA1 cfap45 gRNA2

Phenotypes: Xtr Wt + cfap45 CRISPR (Fig S2 B) [+]

Article Images: [+] show captions
References [+] :
Antony, Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. 2013, Pubmed