Title: NPHP4 Variants Are Associated With Pleiotropic Heart Malformations
Authors: French, Vanessa M ×
van de Laar, Ingrid M B H
Wessels, Marja W
Rohe, Christan
Roos-Hesselink, Jolien W
Wang, Guangliang
Frohn-Mulder, Ingrid M E
Severijnen, Lies-Anne
de Graaf, Bianca M
Schot, Rachel
Breedveld, Guido
Mientjes, Edwin
van Tienhoven, Marianne
Jadot, Elodie
Jiang, Zhengxin
Verkerk, Annemieke
Swagemakers, Sigrid
Venselaar, Hanka
Rahimi, Zohreh
Najmabadi, Hossein
Meijers-Heijboer, Hanne
de Graaff, Esther
Helbing, Wim A
Willemsen, Rob
Devriendt, Koenraad
Belmont, John W
Oostra, Ben A
Amack, Jeffrey D
Bertoli-Avella, Aida M #
Issue Date: Jun-2012
Publisher: Lippincott Williams & Wilkins
Series Title: Circulation Research vol:110 issue:12 pages:1564-1574
Abstract: RationaleCongenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs.ObjectiveTo identify genetic mutations causing cardiac laterality defects.Methods and ResultsWe performed a genome-wide linkage analysis in patients with cardiac laterality defects from a consanguineous family. The patients had combinations of defects that included dextrocardia, transposition of great arteries, double-outlet right ventricle, atrioventricular septal defects, and caval vein abnormalities. Sequencing of positional candidate genes identified mutations in NPHP4. We performed mutation analysis of NPHP4 in 146 unrelated patients with similar cardiac laterality defects. Forty-one percent of these patients also had laterality defects of the abdominal organs. We identified 8 additional missense variants that were absent or very rare in control subjects. To study the role of nphp4 in establishing L-R asymmetry, we used antisense morpholinos to knockdown nphp4 expression in zebrafish. Depletion of nphp4 disrupted L-R patterning as well as cardiac and gut laterality. Cardiac laterality defects were partially rescued by human NPHP4 mRNA, whereas mutant NPHP4 containing genetic variants found in patients failed to rescue. We show that nphp4 is involved in the formation of motile cilia in Kupffer vesicle, which generate asymmetrical fluid flow necessary for normal L-R asymmetry.Conclusions:NPHP4 mutations are associated with cardiac laterality defects and heterotaxy. In zebrafish, nphp4 is essential for the development and function of Kupffer vesicle cilia and is required for global L-R patterning.
ISSN: 0009-7330
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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