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Hum Mutat. 2016 Feb;37(2):194-200. doi: 10.1002/humu.22928. Epub 2015 Dec 2.

A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function.

Author information

1
Hubrecht Institute-KNAW and Medical Physiology, Division Heart and Lungs, University Medical Centre, Utrecht, The Netherlands.
2
Current Address: Department of Biomedical Science and Bateson Centre, University of Sheffield, Sheffield, United Kingdom.
3
Prince Salman Heart Center, King Fahad Medical City, Riyadh, Saudi Arabia.
4
Prince Sultan Cardiac Center, Riyadh, Saudi Arabia.
5
National Guard Hospital, Riyadh, Saudi Arabia.
6
College of Medicine, King Khaled University, Abha, Saudi Arabia.
7
BGI-Shenzhen, Shenzhen, China.
8
Shenzhen Key Laboratory of Genomics, Shenzhen, China.
9
The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzen, China.
10
Department of Anatomy, Embryology & Physiology, Academic Medical Center, The Netherlands.
11
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
12
Laboratoire de Genetique Moleculaire, Service de Genetique Medicale, CHUV, Lausanne, Switzerland.

Abstract

Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects, such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects and may be attributed to incorrect establishment of body laterality. Here, we identify new patients with dextrocardia who have mutations in CFAP53, a coiled-coil domain containing protein. To elucidate the mechanism by which CFAP53 regulates embryonic asymmetry, we used genome editing to generate cfap53 zebrafish mutants. Zebrafish cfap53 mutants have specific defects in organ laterality and randomization of asymmetric gene expression. We show that cfap53 is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ, providing a mechanism by which patients with CFAP53 mutations develop dextrocardia and heterotaxy, and confirming previous evidence that left-right asymmetry in humans is regulated through cilia-driven fluid flow in a laterality organ.

KEYWORDS:

CCDC11; CFAP53; cilia; congenital heart defect; heterotaxy; laterality; zebrafish

PMID:
26531781
DOI:
10.1002/humu.22928
[Indexed for MEDLINE]

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