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. In two separate studies the human genes KMT2A and KMT2B have been associated with CHD. Candidate genes identified in large-scale exome sequencing analyses have been assessed in Drosophila using cardiac-targeted gene silencing of orthologous fly genes. Experiments using the Drosophila ortholog trx support KMT2A and KMT2B as a candidate genes in the development of CHD. For the fly gene, Dmel\trx, many classical amorphic and hypomorphic mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
KMT2A and KMT2B encode histone methyltransferases that methylate Lys-4 of histone H3; H3-K4 methylation represents a specific tag for epigenetic transcriptional activation. As transcriptional coativators, they play critical roles in regulating gene expression during early development and hematopoiesis. The human Hsap\KMT2A gene has been introduced into flies; partial heterologous rescue (functional complementation) has been demonstrated for loss-of-function mutations of trx. KMT2B has not been introduced into flies. KMT2A is also known as MLL; KMT2B is also known as MLL2.
Animals homozygous for amorphic alleles of Dmel\trx die during the embryonic stage. The original allele, thought to result in reduced levels of expression, allows survival to adulthood; homozygous animals exhibit various homeotic phenotypes. Targeted knockdown of trx restricted to the developing heart, effected by RNAi, results in 28-35% lethality prior to the adult stage; abnormal heart morphology is observed in larvae and in surviving adults; adult lifespan is severely reduced. Many physical and genetic interactions of Dmel\trx have been described; see below and in the trx gene report.
[updated Feb. 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]
KMT2B, lysine methyltransferase 2B, encodes a histone methyltransferase that methylates Lys-4 of histone H3. H3 Lys-4 methylation represents a specific tag for epigenetic transcriptional activation. [Gene Cards, KMT2B; 2018.11.13]
KMT2A encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. [Gene Cards, KMT2A; 2021.02.24]
Many to one: 2 human to 1 Drosophila; the second human gene is KMT2A.
Many to one: 2 human to 1 Drosophila; the second human gene is KMT2B.
Moderate-scoring ortholog of human KMT2A and KMT2B (1 Drosophila to 2 human). Dmel\trx shares 21-22% identity and 30-35% similarity with the human genes.
