RFX6: A Key Regulator of Pancreatic Beta Cell Development and Function
Comprehensive genomic and functional analysis of the RFX6 gene, its role in diabetes, and associated disorders
Gene Information Card
| Symbol | RFX6 |
|---|---|
| Full Name | Regulatory Factor X6 |
| Gene Type | Protein coding |
| Chromosomal Location | 6q22.1 |
| NCBI Gene ID | 222546 ncbi.nlm.nih.gov/gene/222546 |
| Ensembl ID | ENSG00000185002 |
| UniProt ID | Q8HWS3 |
| OMIM ID | 612345 |
| HGNC ID | 21478 |
| Aliases | dJ1033B10.3, RFXDC1 |
Description
RFX6 (Regulatory Factor X6) is a member of the regulatory factor X (RFX) family of transcription factors, characterized by a conserved winged-helix DNA-binding domain. It is essential for the development and function of pancreatic beta cells, which produce insulin. RFX6 regulates the expression of genes involved in insulin secretion, beta cell differentiation, and islet morphogenesis. Mutations in RFX6 cause Mitchell-Riley syndrome, a rare autosomal recessive disorder characterized by neonatal diabetes, pancreatic hypoplasia, and intestinal atresia. The gene is also implicated in type 2 diabetes susceptibility and other metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Mitchell-Riley syndrome | Loss-of-function mutations in RFX6 disrupt pancreatic beta cell development, leading to neonatal diabetes and pancreatic agenesis/hypoplasia. | OMIM #615710; PMID: 24656866 |
| Neonatal diabetes mellitus | RFX6 mutations impair insulin production due to defective beta cell differentiation and function. | ClinVar; PMID: 24656866 |
| Type 2 diabetes | Common variants in RFX6 (e.g., rs33933140) are associated with reduced beta cell function and increased risk of type 2 diabetes. | GWAS Catalog; PMID: 24509476 |
| Pancreatic hypoplasia | RFX6 deficiency leads to incomplete pancreatic development, often with exocrine insufficiency. | OMIM #615710; PMID: 24656866 |
| Intestinal atresia | RFX6 mutations are associated with duodenal and jejunal atresia in Mitchell-Riley syndrome. | OMIM #615710; PMID: 24656866 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Pancreas | 12.5 | High |
| Small intestine | 5.2 | Medium |
| Stomach | 3.1 | Low |
| Liver | 1.8 | Low |
| Kidney | 0.9 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| INS-1 (rat beta cell) | 15.3 | High expression; used for functional studies |
| MIN6 (mouse beta cell) | 14.8 | High expression; insulinoma cell line |
| HeLa | 0.2 | Very low expression |
| HEK293 | 0.1 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1069C>T (p.Arg357*) | Nonsense | Rare | Loss of function; truncation of DNA-binding domain; associated with Mitchell-Riley syndrome |
| c.1192C>T (p.Arg398Trp) | Missense | Rare | Loss of function; disrupts transactivation domain; neonatal diabetes |
| c.1465C>T (p.Arg489*) | Nonsense | Rare | Loss of function; premature stop; pancreatic hypoplasia |
| rs33933140 (intronic) | Intronic variant | Common (MAF ~0.05) | Reduced RFX6 expression; associated with type 2 diabetes risk |
Mutation functional classification
Loss of Function (LOF)
Most RFX6 mutations are loss-of-function, leading to haploinsufficiency or complete loss of protein activity, impairing beta cell development and insulin secretion.
Gain of Function (GOF)
No gain-of-function mutations have been reported for RFX6.
Dominant Negative (DN)
Some missense mutations may exert dominant-negative effects by interfering with wild-type RFX6 function, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • regulation of insulin secretion | • pancreatic beta cell development |
| • positive regulation of transcription by RNA polymerase II | • chromatin binding |
Pathways
• Pancreatic beta cell development
• Insulin secretion pathway
• RFX family transcription factor network
• Maturity-onset diabetes of the young (MODY) related pathways
Protein Summary
RFX6 is a 928-amino acid transcription factor containing a conserved RFX DNA-binding domain and a C-terminal transactivation domain. It forms homodimers and heterodimers with other RFX family members to regulate target gene expression. The protein is predominantly nuclear and is critical for the differentiation of pancreatic progenitor cells into insulin-producing beta cells. RFX6 also modulates the expression of genes involved in glucose sensing and insulin granule exocytosis. Structural studies reveal that the DNA-binding domain recognizes X-box motifs in promoter regions of target genes.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| RFX6 Knockout HEK293 Cell Line | EDJ-KQ8265 | Human | 222546 | Details Get a Quote |
| RFX6 Knockout HeLa Cell Line | EDJ-KQ59190 | Human | 222546 | Details Get a Quote |
| RFX6 Knockout A-549 Cell Line | EDJ-KQ67659 | Human | 222546 | Details Get a Quote |
| RFX6 Knockout HCT 116 Cell Line | EDJ-KQ76046 | Human | 222546 | Details Get a Quote |
