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
Citation
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. (2020) Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome. eLIFE. 9:.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping