Glra4, encoding the glycine receptor alpha 4 subunit, is a gene of significance. Glycine receptors are ligand-gated chloride channels mediating inhibitory synaptic transmission in the brain stem and spinal cord [1,4]. The encoded protein of Glra4, although the human ortholog was once considered a pseudogene, is now known to be potentially involved in important biological functions and disease-related processes [2,4].

In a female patient with a de novo Xq22.2 microdeletion that included Glra4, intellectual disability, motor delay, behavioral problems, and craniofacial anomalies were observed, suggesting Glra4 as a candidate gene for these phenotypes [1]. In Glra4 mutant mice, decreased amplitude and delayed onset of the startle response, increased social interaction during the dark period, and changes in anxiety-like behavior were noted, indicating its role in social, startle, and anxiety-like behaviors [2]. Also, in mice, lacking Glra4 inhibits embryonic development to the blastocyst stage, decreases the number of cells in the blastocysts and the litter size, revealing its role in early embryonic development [3].

In conclusion, Glra4 plays important roles in behaviors such as social interaction, startle response, and anxiety-like behavior as shown by mouse models. It is also crucial for early embryonic development in mice. The findings from these model-based studies suggest its potential involvement in human conditions like intellectual disability and craniofacial anomalies, highlighting the value of these genetic models in understanding Glra4's functions and its implications in disease [1,2,3].

References:

1. Labonne, Jonathan D J, Graves, Tyler D, Shen, Yiping, Layman, Lawrence C, Kim, Hyung-Goo. 2016. A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies. In BMC neurology, 16, 132. doi:10.1186/s12883-016-0642-z. https://pubmed.ncbi.nlm.nih.gov/27506666/

2. Darwish, Mohamed, Hattori, Satoko, Nishizono, Hirofumi, Yachie, Nozomu, Takao, Keizo. 2023. Comprehensive behavioral analyses of mice with a glycine receptor alpha 4 deficiency. In Molecular brain, 16, 44. doi:10.1186/s13041-023-01033-x. https://pubmed.ncbi.nlm.nih.gov/37217969/

3. Nishizono, Hirofumi, Darwish, Mohamed, Endo, Takaho A, Abe, Hiroyuki, Yasuda, Ryohei. . Glycine receptor α4 subunit facilitates the early embryonic development in mice. In Reproduction (Cambridge, England), 159, 41. doi:10.1530/REP-19-0312. https://pubmed.ncbi.nlm.nih.gov/31689234/

4. Leacock, Sophie, Syed, Parnayan, James, Victoria M, Lynch, Joseph W, Harvey, Robert J. 2018. Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses. In Frontiers in molecular neuroscience, 11, 23. doi:10.3389/fnmol.2018.00023. https://pubmed.ncbi.nlm.nih.gov/29445326/