This report describes Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (FRTS4); FRTS4 exhibits autosomal dominant inheritance. The human gene implicated in this disease is hepatocyte nuclear factor 4 alpha (HNF4A), which encodes a 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 MODY1, a disease that is similar but without kidney involvement (MIM:125850; FBhh0000480). There is a single orthologous gene in Drosophila, Hnf4, for which deletions, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. 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, but has not been characterized.
Most mutations of HNF4A are implicated in maturity-onset diabetes of the young (MODY1, FBhh0000480); 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; it has been compared with a nearby mutation that corresponds to a human variant implicated in MODY1 ( HNF4A:p.Arg89Trp ).
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R85W in the fly Hnf4 gene (corresponds to R167W in the human HNF4A gene, implicated in FRTS4); R89W in the fly Hnf4 gene (corresponds to R171W in the human HNF4A gene, implicated in MODY1).
Expression of Hnf4 with the FRTS4-associated mutation in Drosophila nephrocytes causes nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The nuclear depletion leads to mitochondrial defects and lipid droplet accumulation; the cytosolic aggregates trigger the expansion of the endoplasmic reticulum (ER), autophagy, and eventually cell death. The cytotoxic effects can be suppressed by inhibiting nuclear exit and proteasomal degradation of the Hnf4 protein. Expression in nephrocytes of Hnf4 with a mutation analogous to the human variant that is implicated in MODY1 did not cause any dominant-negative or cytotoxic effects. It is suggested that MODY1 results from the haploinsufficiency of mutations that result in reduced function of HNF4A, whereas FRTS4 results from dominant-negative effects, in addition.
[updated Feb. 2020 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)
[FANCONI RENOTUBULAR SYNDROME 4 WITH MATURITY-ONSET DIABETES OF THE YOUNG; FRTS4](https://omim.org/entry/616026)
[HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; HNF4A](https://omim.org/entry/600281)
Fanconi syndrome is a disorder of the renal proximal tubules that results in decreased reabsorption of phosphorus, glucose, and amino acids, accompanied by metabolic acidosis secondary to proximal tubular bicarbonate wasting. Children with Fanconi syndrome have classic radiographic evidence of rickets, whereas adults exhibit changes consistent with osteomalacia. (https://www.sciencedirect.com/topics/nursing-and-health-professions/fanconi-renotubular-syndrome).
Fanconi renotubular syndrome is a consequence of decreased solute and water reabsorption in the proximal tubule of the kidney.
Fanconi renotubular syndrome-4 with maturity-onset diabetes of the young (FRTS4) is caused by heterozygous mutation in the HNF4A gene. [from MIM:616026; 2020.02.29]
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 shares 50-53% identity and 63-65% similarity with the human genes.
