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Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish.

Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish.

Authors :
Odelin G
Faucherre A
Marchese D
Pinard A
Jaouadi H
Le Scouarnec S
Chiarelli R
Achouri Y
Faure E
Herbane M
Théron A
Avierinos JF
Jopling C
Collod-Béroud G
Rezsohazy R
Zaffran S
Source :
Nature communications [Nat Commun] 2023 Mar 20; Vol. 14 (1), pp. 1543. Date of Electronic Publication: 2023 Mar 20.
Publication Year :
2023

Abstract

Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5-1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1 <superscript>-1His</superscript> knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1 <superscript>-/-</superscript> mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.<br /> (© 2023. The Author(s).)

Details

Language :
English
ISSN :
2041-1723
Volume :
14
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
36941270
Full Text :
https://doi.org/10.1038/s41467-023-37110-x