Using family-based WGS and other assessments, the human gene LRP2 was identified as possibly implicated in congenital heart defects, specifically in hypoplastic left heart syndrome. LRP2 encodes low density lipoprotein-related protein 2, a protein that plays key role in the re-uptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones; it also has a role in cell-signaling. The most closely related gene in Drosophila is mgl, for which classical loss-of-function alleles, RNAi-targeting constructs, overexpression constructs, and alleles caused by insertional mutagenesis have been generated.
The human LRP2 gene has not been introduced into flies.
Using a driver specific to the developing heart, knockdown of mgl effected by RNAi results in a dilated heart phenotype and arrhythmia, suggesting developmental defects of cardiac structure and function.
[updated Jan. 2021 by FlyBase; FBrf0222196]
A congenital heart defect is a problem with the structure of the heart; it is the most common type of birth defect. The defects can involve the walls of the heart, the valves of the heart, and the arteries and veins near the heart. They can disrupt the normal flow of blood through the heart: the blood flow can slow down, go in the wrong direction or to the wrong place, or be blocked completely (https://medlineplus.gov/congenitalheartdefects.html).
Defects range from simple, which might cause no problems, to complex, which can cause life-threatening complications. The most serious defects are categorized as critical congenital heart defects (CCHD). CCHD is life threatening and requires intervention in infancy; approximately 18 out of 10,000 babies are born with CCHD (https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/PEHDIC/Pages/Newborn-Screening-for-CCHD.aspx).
Genetic causes of congenital heart disease also account for many of the comorbidities seen with increased frequency in congenital heart disease patients, including neurodevelopmental disability, pulmonary disease, arrhythmia, renal disease, heart failure and an increased incidence of malignancy. (Simmons and Brueckner, 2017; pubmed:28872494).
A number of well studied syndromes, including DiGeorge syndrome, Williams-Beuren syndrome, Alagille syndrome, Noonan syndrome, and Holt-Oram syndrome, include congenital heart defect (Pierpont et al., 2007; pubmed:17519398).
Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. [from MIM:306955; 2018.11.13]
LRP2 encodes low density lipoprotein-related protein 2, also called megalin, a multi-ligand endocytic receptor. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones; it also has a role in cell-signaling. [Gene Card, LRP2; 2021.01.11]
Multiple orthologous genes in both species.
Moderate- to high-scoring ortholog of human LRP2; lower-scoring orthologs in both species. Dmel\mgl shares 41% identity and 57% similarity with LRP2.
