Deficiency in hereditary hemorrhagic telangiectasia-associated Endoglin elicits hypoxia-driven heart failure in zebrafish

Abstract

Hereditary hemorrhagic Telangiectasia (HHT) is a rare genetic disease caused by mutations affecting components of Bone Morphogenetic Protein and Transforming Growth Factor-β (BMP/TGF-β) signaling in endothelial cells. This disorder is characterized by arterio-venous malformations which are prone to rupture and the ensuing hemorrhages are responsible for iron deficiency anemia. Along with Activin receptor-like kinase ALK1, mutations in ENDOGLIN are associated with the vast majority of HHT cases. In this report, we characterized zebrafish endoglin locus and demonstrated that it produces two phylogenetically conserved protein isoforms using a distinctive alternative splicing mechanism. Functional analysis of a Crispr/Cas9 zebrafish endoglin mutant revealed that Endoglin deficiency is lethal during the course from juvenile stage to adulthood. Endoglin deficient zebrafish develop cardiomegaly resulting in heart failure and hypochromic anemia which both stem from chronic hypoxia. Furthermore, endoglin mutant zebrafish display structural alterations of the developing gills and underlying vascular network that coincide with hypoxia. Finally, phenylhydrazine treatment demonstrated that lowering hematocrit/blood viscosity alleviates heart failure and enhances survival of Endoglin deficient fish.

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…The targets of studies include lysosomes [ 170 , 171 ], endoplasmic reticulum [ 172 ], membranes [ 173 ], membrane channels [ 174 ], cytoskeleton [ 175 ], recombination processes [ 176 ], aneuploidy [ 177 ], expression regulation [ 178 ], and signaling [ 179 ]. There is research on the genetic basis of the organism’s response to oxidative stress [ 180 , 181 , 182 , 183 , 184 ], hypoxia [ 185 , 186 , 187 ], sodium ion uptake from the surrounding aquatic environment and ammonia excretion [ 188 , 189 , 190 ], inflammation processes [ 191 , 192 ], immunity [ 193 , 194 , 195 , 196 ] and disease resistance [ 197 , 198 , 199 , 200 , 201 ].…”

From mechanisms of heart failure to clinical heart success

“…Thus, research into cardiac development and disease mechanisms is essential to better understand the underlying causes of congenital heart defects, particularly because these relationships are not always obvious. Underscoring this complexity, a Review from Christian Mosimann's group summarises how defects in lateral plate mesoderm development drive syndromic congenital defects of multiple organs, including the heart ( Kocere et al, 2023 ), and a Research article from Lelièvre et al (2023) analyses how mutations in endoglin that are linked to a rare vascular developmental disorder cause congestive heart failure.…”