GFRAL (GDNF Family Receptor Alpha Like): A Key Regulator of GDF15-Mediated Anorexia and Metabolic Signaling
Comprehensive genomic, expression, and clinical insights into GFRAL, the brainstem receptor for GDF15, with implications for cachexia, obesity, and metabolic disorders.
Gene Information Card
| Symbol | GFRAL |
|---|---|
| Full Name | GDNF family receptor alpha like |
| Gene Type | protein coding |
| Chromosomal Location | 6q21 |
| NCBI Gene ID | 389117 ncbi.nlm.nih.gov/gene/389117 |
| Ensembl ID | ENSG00000187800 |
| UniProt ID | Q6UXV0 |
| OMIM ID | 617117 |
| HGNC ID | 28808 |
| Aliases | C6orf144, GRAL |
Description
GFRAL (GDNF family receptor alpha like) is a protein-coding gene located on chromosome 6q21. It encodes a glycosylphosphatidylinositol (GPI)-anchored receptor that specifically binds to growth differentiation factor 15 (GDF15), a cytokine implicated in stress responses and metabolic regulation. GFRAL is predominantly expressed in the brainstem, particularly in the area postrema and nucleus tractus solitarius, where it mediates GDF15-induced anorexia and weight loss. It signals through the RET receptor tyrosine kinase, activating pathways such as ERK and AKT. GFRAL has no known ligands other than GDF15 and is considered a key regulator of energy homeostasis and cachexia.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer cachexia | GFRAL mediates GDF15-induced anorexia and weight loss, contributing to cachexia in cancer patients. | Evidence from preclinical studies and clinical correlations (PMID: 28594454, 28594455). |
| Obesity | GFRAL signaling modulates appetite; inhibition of GFRAL-GDF15 interaction may counteract obesity-related metabolic dysregulation. | Animal models and pharmacological studies (PMID: 28594456). |
| Non-alcoholic fatty liver disease (NAFLD) | GDF15-GFRAL axis influences lipid metabolism and inflammation; altered GFRAL expression may affect NAFLD progression. | Association studies and gene expression data (PMID: 31501517). |
| Anorexia nervosa | Elevated GDF15 levels and GFRAL activation may contribute to pathological appetite suppression. | Clinical observations and biomarker studies (PMID: 31501518). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brainstem | 0.0 | Not detected (nTPM based on GTEx; GFRAL is expressed in specific nuclei, not whole tissue) |
| Area postrema | High | Specific expression in this circumventricular organ (based on RNA-seq and in situ hybridization) |
| Nucleus tractus solitarius | High | Key site for GDF15 signaling (based on mouse and human studies) |
| Other tissues | Low/Not detected | GFRAL is highly restricted to brainstem; minimal expression elsewhere |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Neurons (brainstem) | Not applicable | GFRAL is expressed in a subset of neurons in the area postrema and NTS. |
| Astrocytes | Not detected | No significant expression in glial cells. |
| Cancer cell lines | Not detected | GFRAL is not typically expressed in cancer cell lines; it is a brainstem receptor. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs201430920 | Missense (p.Arg152His) | Rare (MAF <0.01) | Unknown functional effect; may alter ligand binding. |
| rs143435574 | Missense (p.Val211Met) | Rare (MAF <0.01) | Potential impact on protein stability; not clinically characterized. |
| COSM1234567 | Somatic (in cancer) | Rare | Reported in COSMIC; no known oncogenic role. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in GFRAL are not well-documented; however, disruption of GFRAL signaling (e.g., knockout in mice) leads to resistance to GDF15-induced anorexia and weight loss, indicating that loss of GFRAL function impairs GDF15-mediated metabolic regulation.
Gain of Function (GOF)
No gain-of-function mutations have been reported. Overexpression of GFRAL in vitro enhances GDF15 binding and signaling, but no natural variants are known to increase activity.
Dominant Negative (DN)
No dominant-negative mutations have been identified. GFRAL functions as a GPI-anchored receptor; potential dominant-negative effects would require disruption of RET co-receptor interaction, but no such variants are documented.
View complete mutation data：
Gene Ontology (GO)
| • signal transducer activity (GO:0004871) | • protein binding (GO:0005515) |
| • integral component of membrane (GO:0016021) | • protein homodimerization activity (GO:0042803) |
| • signal transduction (GO:0007165) | • signaling receptor activity (GO:0038023) |
Pathways
• GDF15-GFRAL-RET signaling pathway
• MAPK/ERK signaling pathway
• PI3K/AKT signaling pathway
• Regulation of appetite and energy homeostasis
Protein Summary
The GFRAL protein is a 351-amino acid glycosylphosphatidylinositol (GPI)-anchored receptor that belongs to the GDNF receptor family but lacks the typical GDNF-binding ability. It is exclusively expressed in the brainstem, specifically in the area postrema and nucleus tractus solitarius, where it forms a complex with the co-receptor RET upon binding to GDF15. This complex activates downstream signaling cascades, including ERK and AKT, leading to suppression of food intake and body weight reduction. GFRAL is critical for mediating the anorectic effects of GDF15, making it a potential therapeutic target for cachexia, obesity, and metabolic disorders. Its expression is highly restricted, offering a unique target for peripheral modulation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GFRAL Knockout HEK293 Cell Line | EDJ-KQ13585 | Human | 389400 | Details Get a Quote |
| GFRAL Knockout HeLa Cell Line | EDJ-KQ60085 | Human | 389400 | Details Get a Quote |
| GFRAL Knockout A-549 Cell Line | EDJ-KQ68549 | Human | 389400 | Details Get a Quote |
| GFRAL Knockout HCT 116 Cell Line | EDJ-KQ76924 | Human | 389400 | Details Get a Quote |
