Initially identified as a candidate susceptibility gene based on genome-wide association studies, results in Drosophila support the proposal that the human gene GLIS3 is a susceptibility locus for type 2 diabetes mellitus. GLIS3 is a zinc-finger transcription factor involved in the development of pancreatic islet beta cells, the thyroid, eye, liver and kidney. GLIS3 is also implicated in neonatal diabetes mellitus with congenital hypothyroidism syndrome (NDH syndrome; MIM:610199), a severe autosomal recessive disorder. There is a single gene orthologous to GLIS3 in Drosophila, lmd, for which classical amorphic and hypomorphic alleles and RNAi-targeting constructs have been generated. Dmel\lmd is also orthologous to a second human gene, GLIS1.
The human GLIS3 gene has not been introduced into flies.
Animals homozygous for amorphic alleles of Dmel\lmd show defects in myoblast fusion and somatic muscle development and die as late embryos. A single physical interaction for Dmel\lmd has been described; see below and in the gene report for lmd.
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 lmd in Drosophila adult IPCs severely reduced levels of Ilp2 mRNA, total protein, and circulating protein.
[updated Jan. 2017 by FlyBase; FBrf0222196]
GLIS3 is associated with Type 2 diabetes and Type 1 diabetes in multiple GWAS studies (see GWAS Catalog, below in 'External links').
GLIS3 encodes a member of the GLI-similar zinc finger protein family. It functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, the thyroid, eye, liver and kidney. (NCBI Gene, GLIS3; 2017.01.19]
GLIS3 directly transactivates the neurogenin 3 promoter, as well as the insulin promoter, and controls β-cell expansion through transcriptional control of the cell cycle gene CCND2 (Schwitzgebel, 2014; pubmed:24843749).
Many to one: 2 human to 1 Drosophila; additional human gene is GLIS1.
High- to moderate-scoring ortholog of human GLIS3 and GLIS1 (1 Drosophila to 2 human). Dmel\lmd is 30% identical and 38% similar to GLIS3, with 78-91% identity in the zinc finger domains.
