Alternative titles; symbols
HGNC Approved Gene Symbol: FEZ1
Cytogenetic location: 11q24.2 Genomic coordinates (GRCh38): 11:125,442,881-125,496,265 (from NCBI)
The C. elegans gene unc-76 ('unc' for 'uncoordinated') is necessary for normal axonal bundling and elongation within axon bundles. By searching an EST database with the unc-76 sequence, Bloom and Horvitz (1997) identified 2 human genes with sequence similarity to unc-76; they named these novel genes FEZ1 and FEZ2 (604826). The deduced 392-amino acid FEZ1 protein shares 35% amino acid identity with C. elegans unc-76, with 3 regions in the C-terminal halves showing the most similarity. The N-terminal half of FEZ1 is highly acidic, and large regions of the protein are predicted to form amphipathic helices. FEZ1 lacks a potential signal sequence and transmembrane domains, suggesting that it is located intracellularly. Bloom and Horvitz (1997) identified human ESTs encoding a predicted 104-amino acid C-terminally truncated form of FEZ1, which they named FEZ1-T. They stated that FEZ1-T is likely a product of alternative splicing. The authors noted that most of the FEZ1 ESTs that they identified are derived from brain.
Bloom and Horvitz (1997) demonstrated that expression of the human FEZ1 gene in C. elegans unc-76 mutants could restore to the mutants partial locomotion and axonal fasciculation, suggesting that FEZ1, like unc-76, functions in axonal outgrowth.
Using quantitative PCR and Western blot analysis, Haedicke et al. (2009) showed that neurons expressed high levels of FEZ1 compared with astrocytes and microglia and were correspondingly less susceptible to infection with pseudotyped human immunodeficiency virus (HIV)-1 (see 609423). Knockdown of FEZ1 via small interfering RNA reduced resistance to HIV-1 infection, whereas FEZ1 overexpression increased resistance in susceptible cell types, such as microglia. Neither IFNA (147660) nor IFNG (147570) induced FEZ1 expression in brain macrophages. Haedicke et al. (2009) concluded that FEZ1 appears to represent a unique neuron-specific determinant of cellular susceptibility to infection in an HIV-1-resistant cell type.
The International Radiation Hybrid Mapping Consortium mapped the FEZ1 gene to chromosome 11 (SHGC-32309).
Sakae et al. (2008) found that Fez1 was exclusively expressed in the mouse central nervous system beginning in the prenatal period with peak expression at postnatal day 10. Expression was also detected in adult animals. In the brain, Fez1 was found in GABAergic inhibitory neurons in various regions, including the hippocampus, neocortex, caudate-putamen, and nucleus accumbens. In the hippocampal dentate gyrus, Fez1 was present along axon bundles of granule cells. Fez1-null mice had no structural brain anomalies but showed behavioral changes, including hyperlocomotion and increased sensitivity to psychostimulants, which was associated with increased dopamine release in the nucleus accumbens compared to controls. These findings suggested that enhanced mesolimbic dopaminergic transmission contributed to the hyperactivity. Fez1-null mice did not show increased anxiety, learning or memory deficits, or sensorimotor gating defects when compared to wildtype mice. Sakae et al. (2008) noted that FEZ1 interacts with DISC1 (605210), and postulated a role for FEZ1 in schizophrenia.
Bloom, L., Horvitz, H. R. The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation. Proc. Nat. Acad. Sci. 94: 3414-3419, 1997. [PubMed: 9096408] [Full Text: https://doi.org/10.1073/pnas.94.7.3414]
Haedicke, J., Brown, C., Naghavi, M. H. The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection. Proc. Nat. Acad. Sci. 106: 14040-14045, 2009. [PubMed: 19667186] [Full Text: https://doi.org/10.1073/pnas.0900502106]
Sakae, N., Yamasaki, N., Kitaichi, K., Fukuda, T., Yamada, M., Yoshikawa, H., Hiranita, T., Tatsumi, Y., Kira, J., Yamamoto, T., Miyakawa, T., Nakayama, K. I. Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. Hum. Molec. Genet. 17: 3191-3203, 2008. [PubMed: 18647754] [Full Text: https://doi.org/10.1093/hmg/ddn215]