Initially identified as a candidate susceptibility gene based on genome-wide association studies, results in Drosophila support the proposal that the human gene BCL11A is a susceptibility locus for type 2 diabetes mellitus.
BCL11A is a zinc-finger transcription factor that is highly expressed in the brain, B-lymphocytes, and the adult erythroid lineage BCL11A is also implicated in Dias-Logan syndrome (MIM:617101), characterized by global developmental delay and intellectual disability associated with persistence of fetal hemoglobin. There is a single gene orthologous to BCL11A in Drosophila, Cph, for which multiple genetic reagents have been generated, including RNAi-targeting constructs and alleles caused by insertional mutagenesis. Dmel\Cph is also orthologous to a second human gene, BCL11B.
The human BCL11A gene has not been introduced into flies.
Most insertional mutations of Dmel\Cph are lethal when homozygous.
Drosophila insulin producing cells (IPCs) synthesize and secrete insulin-like peptides (Ilp2, Ilp3, Ilp5) when exposed to glucose; they appear to be analogous to mammalian pancreatic islet beta cells. Development of functional tagged forms of the insulin-like peptide gene Ilp2 has allowed independent assessment of the expression, production, and secretion of insulin-like peptides by the IPCs (FBrf0225849). Using a UAS-RNAi construct, knockdown of Cph in Drosophila adult IPCs increased circulating levels of Ilp2, without affecting mRNA levels, suggesting that Cph may play a role in regulating Ilp2 protein levels post-translationally.
[updated Apr. 2024 by FlyBase; FBrf0222196]
BCL11A is associated with Type 2 diabetes in a GWAS study (see GWAS Catalog, below in 'External links').
The BCL11A gene encodes a zinc finger protein that regulates transcription through interaction with COUP-TF proteins, as well as direct, sequence-dependent DNA binding (Wiegreffe et al., 2015; pubmed:26182416). It is highly expressed in the brain, B-lymphocytes, and the adult erythroid lineage (summary by Funnell et al., 2015; pubmed:26019277). [from MIM:606557; 2017.01.20]
Many to one: 2 human to 1 Drosophila; additional human gene is BCL11B.
Moderate-scoring ortholog of human BCL11A and BCL11B (1 Drosophila to 2 human). Dmel\lmd is 26-27% identical and 35-36% similar to the human genes, with 45-95% identity in the zinc finger domains.
