PUBLICATION

Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome

Authors
Theis, J.L., Vogler, G., Missinato, M.A., Li, X., Nielsen, T., Zeng, X.I., Martinez-Fernandez, A., Walls, S.M., Kervadec, A., Kezos, J.N., Birker, K., Evans, J.M., O'Byrne, M.M., Fogarty, Z.C., Terzic, A., Grossfeld, P., Ocorr, K., Nelson, T.J., Olson, T.M., Colas, A.R., Bodmer, R.
ID
ZDB-PUB-201003-9
Date
2020
Source
eLIFE   9: (Journal)
Registered Authors
Zeng, Sean
Keywords
D. melanogaster, genetics, genomics, human, medicine, zebrafish
MeSH Terms
  • Animals
  • Drosophila melanogaster/genetics
  • Drosophila melanogaster/growth & development
  • Female
  • Heart/growth & development
  • Humans
  • Hypoplastic Left Heart Syndrome/genetics*
  • Low Density Lipoprotein Receptor-Related Protein-2/genetics*
  • Low Density Lipoprotein Receptor-Related Protein-2/metabolism
  • Male
  • Zebrafish/genetics
  • Zebrafish/growth & development
PubMed
33006316 Full text @ Elife
Abstract
Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multi-disciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in generic human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband's iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps towards deciphering oligogenic underpinnings of CHDs, including maladaptive left hearts.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping