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Mutations in the human HNF4A gene lead to Maturity Onset Diabetes of the Young 1 (MODY1), a form of type 2 diabetes that patients develop around 20 to 40 years of age . No homozygous mutations in human HNF4A have been reported, consistent with the embryonic lethality in mouse . Infants heterozygous for HNF4A may exhibit macrosomia (high weight), hyperinsulinemia and hypoglycemia at birth, and it has been recommended that newborns with those symptoms, and a family history of diabetes, be screened for mutations in HNF4A .
Dozens of mutations (and SNPs) associated with diabetes have been mapped in the coding region of HNF4A as well as the P2 but not the P1 promoter, consistent with the P2 promoter driving expression of HNF4α in the beta cells of the pancreas .
Tissue-specific knockouts of the Hnf4a gene in mice have been created in liver, colon and pancreatic beta cells. The embryonic liver-specific knockout shows that HNF4α is required for the initial epithelial transformation of the fetal liver . The adult liver-specific knockout indicates that HNF4α is required for maintenance of the hepatic phenotype, including lipid homeostasis . The mice have a fatty liver and die within 6 weeks. Intestine/colon-specific knockouts in both the embryo and the adult verify that HNF4α is also required for the development and proper functioning of the gut ; lower levels of HNF4α have also been noted in humans with inflammatory bowel (Crohn's) disease as well as a mouse model for experimental colitis . Two beta-cell-specific knockouts confirmed a role for HNF4α in regulating the insulin secretion pathway, although some discrepancies were noted .
MeSH cloud (automatically populated)
About this section
The MeSH cloud below displays MeSH terms that are associated with this transcription factor. The physical size of the terms reflect the significance of their association with the transcription factor as determined by the Fisher's Exact Test. It should be noted that these associations do not necessarily imply a positive correlation between the described MeSH term and this transcription factor. For instance, if the MeSH term "apoptosis" occurs, it may indicate that this transcription factor can induce apoptosis (positive correlation), or prevent apoptosis (negative correlation). Methods: The transcription factor is mapped to a set of Pubmed publications through the gene-to-pubmed association as provided by NCBI. Then, a collection of MeSH terms associated with the papers are compiled, along with the frequency of each MeSH term. The Fisher's Exact Test is conducted on the frequency of each term in the collection, versus its average frequency, to determine its significance in the collection. More information on MeSH can be found on the MeSH homepage.
Carcinoma, Hepatocellular Cystadenocarcinoma, Mucinous Cystadenoma, Mucinous Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 Diabetic Nephropathies Fetal Macrosomia Genetic Predisposition to Disease Glucose Intolerance Hepatoblastoma Metabolic Syndrome X Persistent Hyperinsulinemia Hypoglycemia of Infancy Prediabetic State Stomach Neoplasms
MGI mammalian phenotype terms (automatically populated)
no abnormal phenotype detected (MP:0002169) abnormal liver morphology (MP:0000598) abnormal hepatocyte morphology (MP:0000607) abnormal liver development (MP:0000596) dissociated hepatocytes (MP:0000608) decreased glycogen level (MP:0005439) abnormal embryogenesis/ development (MP:0001672) abnormal embryonic tissue morphology (MP:0002085) abnormal extraembryonic tissue morphology (MP:0002086) abnormal gastrulation (MP:0001695) abnormal primitive streak formation (MP:0002230) abnormal ectoderm development (MP:0001675) abnormal yolk sac morphology (MP:0001718) absent mesoderm (MP:0001683) absent amnion (MP:0005030) absent allantois (MP:0003087) embryonic lethality during organogenesis (MP:0006207) increased ectoderm apoptosis (MP:0003895) embryonic growth retardation (MP:0003984) absent chorion (MP:0009593) impaired glucose tolerance (MP:0005293) abnormal lipid homeostasis (MP:0002118) increased circulating ketone body level (MP:0002575) hepatic steatosis (MP:0002628) decreased circulating triglyceride level (MP:0002644) decreased circulating free fatty acid level (MP:0002702) decreased circulating cholesterol level (MP:0005179) increased circulating bilirubin level (MP:0005344) hypokalemia (MP:0004119) hypoferremia (MP:0004151) decreased circulating insulin level (MP:0002727) abnormal channel response (MP:0003484) prenatal lethality (MP:0002080) premature death (MP:0002083) enlarged liver (MP:0000599) weight loss (MP:0001263) decreased circulating HDL cholesterol level (MP:0000186) decreased embryo size (MP:0001698) increased apoptosis (MP:0006042)
About this section
Data displayed in this section is derived from the Mouse Genome Database (MGD). For more information, see Eppig JT, Bult CJ, Kadin JA, Richardson JE, Blake JA, and the members of the Mouse Genome Database Group. 2005. The Mouse Genome Database (MGD): from genes to mice-a community resource for mouse biology. Nucleic Acids Res 2005; 33: D471-D475.