hoxa1a -Null Zebrafish as a Model for Studying HOXA1 -Associated Heart Malformation in Bosley-Salih-Alorainy Syndrome.

Mutations in HOXA1 can lead to diseases such as Bosley-Salih-Alorainy syndrome, involving severe cardiovascular malformations. However, the role of HOXA1 in cardiac morphogenesis remains unclear. hoxa1a is a homologous gene to human HOXA1 in zebrafish. We used CRISPR to make hoxa1a -null zebrafish that exhibited multiple heart malformations. In situ hybridization and sections revealed the morphological changes in mutants: enlarged ventricle with thickened myocardium and increased trabeculae, intensified OFT and inadequate heart looping, with electrocardiography supporting these pathological changes. High-speed photography captured cardiac pumping and revealed a significant decrease in cardiac output. Furthermore, lacking hoxa1a led to posterior body abnormality that affected movement ability, corresponding with the motor development delay in patients. Upregulation of hox paralogues in hoxa1a -null fish implied a compensatory mechanism between hox genes. Accordingly, we successfully constructed a hoxa1a -null model with a cardiac disease pattern which occurred in human HOXA1 -associated heart malformation. The study of hoxa1a in zebrafish can further promote the understanding of hox genes and related diseases.