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

Animals Body Patterning / genetics Cilia / genetics Heart Defects, Congenital / genetics Heterotaxy Syndrome / genetics Mutation, Missense Phenotype Xenopus / abnormalities Xenopus Proteins / metabolism
CFAP45 Cilia Congenital heart disease Heterotaxy Xenopus

Journal

Developmental biology
ISSN: 1095-564X
Titre abrégé: Dev Biol
Pays: United States
ID NLM: 0372762

Informations de publication

Date de publication:
07 2023
Historique:
received: 17 01 2023
revised: 07 04 2023
accepted: 23 04 2023
medline: 2 6 2023
pubmed: 13 5 2023
entrez: 12 5 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ydbio.2023.04.006 PMID: 37172641 PMC: PMC10373286
pubmed: 37172641
pii: S0012-1606(23)00067-2
doi: 10.1016/j.ydbio.2023.04.006
pmc: PMC10373286
mid: NIHMS1904232
pii:
doi:

Substances chimiques

Xenopus Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

75-88

Subventions

Organisme : NICHD NIH HHS
ID : R01 HD102186
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS127879
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest SAL and MKK are co-founders of Victory Genomics, Inc.

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Auteurs

E Deniz (E)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. Electronic address: engin.deniz@yale.edu.

M Pasha (M)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

M E Guerra (ME)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

S Viviano (S)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

W Ji (W)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

M Konstantino (M)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

L Jeffries (L)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

S A Lakhani (SA)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

L Medne (L)

Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, USA.

C Skraban (C)

Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, USA.

I Krantz (I)

Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, USA.

M K Khokha (MK)

Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. Electronic address: mustafa.khokha@yale.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Morphogenèse › Plan d'organisation du corps › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Cellules › Structures cellulaires › Prolongements cytoplasmiques › Cils vibratiles › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations cardiovasculaires › Cardiopathies congénitales › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations cardiovasculaires › Cardiopathies congénitales › Syndrome d'hétérotaxie › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation faux-sens › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Amphibiens › Anura › Pipidae › Xenopus › CFAP45, a heterotaxy and congenital heart...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines d'amphibien › Protéines de Xénope › CFAP45, a heterotaxy and congenital heart...