Congenital heart defect (CHD), also described as congenital heart disease, is the most common type of birth defect; it is thought to have a significant genetic component. Candidate genes identified in a large-scale exome sequencing analysis have been assessed in a fly system using cardiac-targeted gene silencing of orthologous fly genes. Experiments using the Drosophila ortholog SREBP support SREBF1 as a candidate gene in the development of CHD.
SREBF1 encodes a bHLH-Zip transcription factor involved in sterol biosynthesis. There a single orthologous gene in Drosophila, SREBP; Dmel\SREBP is also ortholgous to a second gene in human, SREBF2. The human SREBF1 gene has not been introduced into flies.
Animals homozygous or hemizygous for amorphic alleles of Dmel\SREBP typically die in early larval stage. Targeted knockdown of SREBP restricted to the developing heart, effected by RNAi, results in 20% lethality prior to the adult stage. Expression of a constitutively active form of Dmel\SREBP in the heart results in cardiac arrhythmia phenotypes; in the adult heart significant loss of longitudinal fibers, and disarrayed inner transverse myofibrils are observed. Physical and genetic interactions of Dmel\SREBP have been described; see below and in the SREBP gene report.
[updated May 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]
SREBF1 encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor that binds to the sterol regulatory element-1 (SRE1), a motif that is found in the promoter of the low density lipoprotein receptor gene and other genes involved in sterol biosynthesis. [Gene Cards, SREBF1; 2021.05.15]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human SREBF1 and SREBF2 (1 Drosophila to 2 human). Dmel\SREBP shares 31-32% identity and 44-47% similarity with the human genes.
