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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(): e59554.
FlyBase ID
FBrf0247040
Publication Type
Research paper
Abstract

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary 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 healthy 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 toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

PubMed ID
PubMed Central ID
PMC7581429 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    eLife
    Title
    eLife
    ISBN/ISSN
    2050-084X
    Data From Reference