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FB2026_01
,
released March 12, 2026
This report describes maturity-onset diabetes of the young, type 1 (MODY1); MODY1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is hepatocyte nuclear factor 4 alpha (HNF4A), which encodes a nuclear transcription factor that is known to regulate expression of several hepatic genes and may play a role in development of the liver, kidney, and intestines. HNF4A is also implicated in several other diabetes-related diseases (see MIM:600281). There is a single orthologous gene in Drosophila, Hnf4, for which multiple genetic reagents have been generated, including deletions, RNAi-targeting constructs, and alleles caused by insertional mutagenesis. Dmel\Hnf4 is also orthologous to a second gene in human, HNF4G.
A UAS construct of a wild-type human Hsap\HNF4A gene has been introduced into flies and is available, but has not been characterized to date.
Animals that are transheterozygous for two small overlapping deletions in the region of the Dmel\Hnf4 gene produce no detectable Hnf4 protein. This genotype recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). Typically, the animals die before or within a day of eclosion; reducing the sugar content of their diet allows survival to extend for several weeks into the adult stage.
Variants implicated in MODY1 have been assessed using analogous mutations in fly gene; see the 'Disease-Implicated Variants' table below.
Although most mutations of HNF4A are implicated in MODY1, one mutation ( HNF4A:p.Arg85Trp ) in the DNA-binding domain causes additional phenotypes of renal Fanconi syndrome (FRTS). This pathogenic variant has been characterized using the analogous mutation in the Drosophila Hnf4 gene; see the human disease model report 'Fanconi renotubular syndrome 4 with MODY' (FBhh0001203). Using the analogous mutations in Dmel\Hnf4, phenotypes of the FRTS4 pathogenic variant has been compared with a nearby mutation that corresponds to a human variant implicated in MODY1 ( HNF4A:p.Arg89Trp ).
[updated Aug. 2021 by FlyBase; FBrf0222196]
Maturity-onset diabetes of the young is defined as an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Since there is increasing incidence of polygenic type 2 diabetes in childhood and adolescence, and patients with gene mutations characteristic of MODY often present with clinical diabetes later in life, substituting the term 'autosomal dominant type 2 diabetes' has been proposed. [from MIM:606391; 2017.01.23]
Noninsulin-dependent diabetes mellitus is distinct from MODY in that it is polygenic, characterized by gene-gene and gene-environment interactions with onset in adulthood, usually at age 40 to 60 but occasionally in adolescence if a person is obese. [from MIM:125853; 2017.01.23]
Up to 5% of all diabetes cases may be due to MODY. (http://www.health.harvard.edu/diabetes/maturity-onset-diabetes-of-the-young-mody)
[MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1; MODY1](https://omim.org/entry/125850)
[HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; HNF4A](https://omim.org/entry/600281)
MODY, type 1, is typically a mild form of diabetes, with mild elevations in fasting plasma glucose concentrations. Hyperglycemia tends to increase over time, resulting in the need for treatment with oral hypoglycemic drugs or insulin in many patients. Microvascular complications, particularly those involving the retina or kidneys, are as common in these patients as in patients with type 1 or type 2 diabetes (matched according to the duration of diabetes and the degree of glycemic control) and are probably determined by the degree of glycemic control. [from MIM:125850; 2017.01.23]
Type 1 maturity-onset diabetes of the young (MODY) can be caused by mutation in the gene encoding hepatocyte nuclear factor-4-alpha (HNF4A); it is inherited as an autosomal dominant. [from MIM:125850; 2017.01.23]
The protein encoded by the hepatocyte nuclear factor 4 alpha (HNF4A) gene is a ligand-dependent DNA-binding transcription factor which binds DNA as a homodimer; it known to regulate expression of several hepatic genes and may play a role in development of the liver, kidney, and intestines. [from Gene Cards, HNF4A; 2017.01.23]
Hepatocyte nuclear factor-4-alpha (HNF4A) is a member of the nuclear receptor family of transcription factors and is the most abundant DNA-binding protein in the liver, where it regulates genes largely involved in the hepatic gluconeogenic program and lipid metabolism (summary by Chandra et al., 2013; pubmed:23485969). [from MIM:600281; 2017.01.23]
Many to one: 2 human to 1 Drosophila; additional human gene is HNF4G.
High-scoring ortholog of human HNF4G and HNF4A (1 Drosophila to 2 human). Dmel\Hnf4 is 50-53% identical and 63-65% similar to the human genes.