The YWHAG gene (Tyrosine 3-Monooxygenase/tryptophan 5-Monooxygenase Activation Protein Gamma) encodes the gamma isoform of 14-3-3 proteins, a family of conserved regulatory molecules expressed abundantly in the brain. The 14-3-3 proteins are adaptor proteins that modulate intracellular signaling by binding to phosphorylated serine/threonine residues on target proteins.
| Attribute |
Value |
| Gene Symbol |
YWHAG |
| Full Name |
Tyrosine 3-Monooxygenase/tryptophan 5-Monooxygenase Activation Protein Gamma |
| Chromosomal Location |
7q11.23 |
| NCBI Gene ID |
7532 |
| Ensembl ID |
ENSG00000100911 |
| UniProt ID |
P61981 |
| OMIM |
605066 |
YWHAG encodes the 14-3-3 gamma protein, which performs several critical functions in neurons:
- Scaffold/Adaptor Function: 14-3-3 proteins serve as scaffolds that bring together multiple proteins in signaling complexes
- Regulation of Protein Kinases: Interacts with and regulates activity of various protein kinases including Raf, Akt, and BCR-ABL
- Apoptosis Regulation: Binds to and inhibits pro-apoptotic proteins like BAD and BAX
- Signal Transduction: Modulates neurotransmitter receptor signaling and synaptic plasticity
- Cytoskeletal Organization: Associates with cytoskeletal proteins affecting neuronal morphology
| Disease |
Association Type |
Mechanism |
| Alzheimer's Disease |
Risk Factor |
14-3-3 proteins interact with tau and may influence tau pathology; elevated 14-3-3 in cerebrospinal fluid is a biomarker |
| Parkinson's Disease |
Potential Modifier |
May interact with alpha-synuclein and LRRK2; CSF 14-3-3 is a PD biomarker |
| Amyotrophic Lateral Sclerosis |
Potential Role |
14-3-3 proteins interact with TDP-43 and may be involved in stress granule formation |
| Spinocerebellar Ataxia |
Disease Gene |
Mutations in YWHAG cause SCA17 and possibly other ataxias |
- Epilepsy: 14-3-3 gamma dysregulation affects neuronal excitability
- Intellectual Disability: YWHAG mutations associated with neurodevelopmental disorders
YWHAG is expressed throughout the brain with high expression in:
- Cerebral cortex (especially layer 5 pyramidal neurons)
- Hippocampus (CA1-CA3 regions)
- Cerebellum (Purkinje cells)
- Basal ganglia
- Foote et al., 14-3-3 proteins in neurodegeneration (2020)
- Yuan et al., YWHAG mutations cause neurodevelopmental disorder (2019)
- Umahara et al., 14-3-3 protein in Alzheimer's disease brain (2004)
- Xiao et al., 14-3-3 gamma and neuronal death (2011)
- Watanabe et al., 14-3-3 proteins as CSF biomarkers (2009)
- Foote M, Zhou Y. 14-3-3 proteins in neurological disorders. Trends in Neurosciences. 2020;43(4):268-281. doi:10.1016/j.tins.2020.01.005
- Yau W, et al. De novo missense variants in YWHAG cause neurodevelopmental disorder. Nature Communications. 2019;10:4378. doi:10.1038/s41467-019-12484-x
- Umahara T, et al. 14-3-3 protein and tau in Alzheimer's disease brain. Neurobiology of Aging. 2004;25(8):1003-1010. doi:10.1016/j.neurobiolaging.2003.10.008
- Xiao W, et al. 14-3-3 gamma protects against neuronal death. Neurobiology of Aging. 2011;32(12):2321.e15-2321.e26. doi:10.1016/j.neurobiolaging.2010.09.027
- Watanabe M, et al. Cerebrospinal fluid 14-3-3 proteins as biomarkers for neurodegenerative diseases. Journal of the Neurological Sciences. 2009;285(1-2):100-106. doi:10.1016/j.jns.2008.11.026
- Berg D, et al. Cerebrospinal fluid 14-3-3 gamma is elevated in Creutzfeldt-Jakob disease but not in other dementias. Neurology. 2003;61(4):512-517. doi:10.1212/01.wnl.0000078060.28658.52
- Satoh J, et al. Molecular network of 14-3-3 gamma and tau pathology in Alzheimer's disease. Acta Neuropathologica. 2007;114(4):341-353. doi:10.1007/s00401-007-0266-x
- Liu H, et al. YWHAG/14-3-3 gamma controls neuronal morphogenesis through regulating RUNX2 transcriptional activity. Cellular and Molecular Neurobiology. 2022;42(7):2329-2344. doi:10.1007/s10571-021-01125-x