Contribution of LRP1 in Human Congenital Heart Disease Correlates with Its Roles in the Outflow Tract and Atrioventricular Cushion Development

Genes (Basel). 2023 Apr 21;14(4):947. doi: 10.3390/genes14040947.


Due to the prevalence of congenital heart disease in the human population, determining the role of variants in congenital heart disease (CHD) can give a better understanding of the cause of the disorder. A homozygous missense mutation in the LDL receptor-related protein 1 (Lrp1) in mice was shown to cause congenital heart defects, including atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV). Integrative analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets and spatial transcriptomics of human and mouse hearts indicated that LRP1 is predominantly expressed in mesenchymal cells and mainly located in the developing outflow tract and atrioventricular cushion. Gene burden analysis of 1922 CHD individuals versus 2602 controls with whole-exome sequencing showed a significant excess of rare damaging LRP1 mutations in CHD (odds ratio (OR) = 2.22, p = 1.92 × 10-4), especially in conotruncal defect with OR of 2.37 (p = 1.77 × 10-3) and atrioventricular septal defect with OR of 3.14 (p = 0.0194). Interestingly, there is a significant relationship between those variants that have an allele frequency below 0.01% and atrioventricular septal defect, which is the phenotype observed previously in a homozygous N-ethyl-N-nitrosourea (ENU)-induced Lrp1 mutant mouse line.

Keywords: LRP1; atrioventricular cushion; congenital heart defect; outflow tract.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Heart Defects, Congenital* / genetics
  • Heart Septal Defects* / genetics
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Mice
  • Mutation
  • Phenotype


  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse

Supplementary concepts

  • Atrioventricular Septal Defect

Grants and funding

This work is supported by the American Heart Association (17SDG33670982) and the University of Pittsburgh (JHL).