HGNC Approved Gene Symbol: GAS2
Cytogenetic location: 11p14.3 Genomic coordinates (GRCh38) : 11:22,626,002-22,813,055 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p14.3 | ?Deafness, autosomal recessive 125 | 620877 | Autosomal recessive | 3 |
Schneider et al. (1988) identified a group of genes that are highly expressed during growth arrest in murine fibroblasts. Brancolini et al. (1992) characterized one of those genes, Gas2, in mouse. Using immunofluorescence, they found that Gas2 is a component of the microfilament system. Gas2 colocalizes with actin fibers at the cell border and along the stress fibers in growth-arrested mouse fibroblasts. On Western blots of both human and mouse fibroblast extracts, antibodies against Gas2 recognized a 36-kD protein.
By screening a human kidney library with a fragment of the mouse Gas2 cDNA, Collavin et al. (1998) isolated cDNAs encoding human GAS2. The predicted 313-amino acid human protein differs in only 8 residues from mouse Gas2. When expressed in mammalian cells, human GAS2 localized at the actin cytoskeleton, along the stress fibers and at the plasma membrane. Like the mouse protein, GAS2 is proteolytically cleaved in apoptotic cells. Using RT-PCR and Western blot analysis, Collavin et al. (1998) determined that GAS2 was expressed in most of the tissues analyzed, with the highest levels of protein found in liver, lung, and kidney.
Chen et al. (2021) analyzed Gas2 expression in the inner ear of mouse embryos and observed prominent sites of staining along the medial and lateral walls of the otic vesicle and cochlear duct, marking progenitors of the sensory epithelium and stria vascularis, respectively. Robust GAS2 expression was also detected in the organ of Corti at postnatal stages, including pillar cells at postnatal day 3 (P3) and Deiters cells at P5. GAS2 staining persisted in inner and outer pillar cells as they separated from each other to form the tunnel of Corti at P7 and as they matured into adulthood. Gas2 expression was also detected in the stria vascularis, spiral prominence, and greater epithelial ridge, and was notably absent from hair cells and spiral ganglion neurons.
Colombo et al. (1992) showed that the Gas2 gene is linked to markers on mouse chromosome 7. By fluorescence in situ hybridization and by analysis of a radiation hybrid panel, Collavin et al. (1998) mapped the human GAS2 gene to 11p15.2-p14.3, a region that has homology of synteny with mouse chromosomal band 7C.
To determine whether GAS2 associates with cytoskeletal elements in the inner ear, Chen et al. (2021) performed coimmunolabeling experiments for GAS2 and alpha-tubulin (see 602529) on mouse cochlear preparations at P14 and P25. Extensive colocalization of GAS2 and detyrosinated alpha-tubulin staining was evident along the length of microtubule bundles in the heads of inner and outer pillar cells, as well as Dieters cell phalangeal processes extending between rows of outer hair cells. Almost all of the colocalization occurred on microtubule bundles at the apical surface (head) of inner and outer pillar cells, and the colocalization persisted in the head, body, and feet of inner and outer pillar cells into adulthood. The authors suggested that GAS2 might play a role in the organization of cytoskeletal specialization in cochlear supporting cells.
In 4 brothers of Somalian ancestry with congenital nonsyndromic sensorineural deafness (DFNB125; 620877), Chen et al. (2021) identified homozygosity for a splice site mutation in the GAS2 gene (602835.0001). The mutation segregated fully with disease in the family and was not found in more than 15,000 exomes in an in-house database or in the gnomAD database. Functional analysis showed that the mutation causes retention of intron 6, which was predicted to result in a premature termination codon.
Using targeted embryonic stem cells, Chen et al. (2021) generated Gas2-knockout mice. Although the mutant embryos showed no overt signs of inner ear dysmorphology, the knockout mice displayed severe hearing loss. Immunostaining of whole-mount cochlear preparations revealed loss of microtubules within the apical surface of pillar cells (supporting cells of the inner ear) beginning at P14 in mutant mice and progressing to nearly 70% depletion by P25 compared to control mice. Almost all microtubules were lost from inner pillar cell heads at P60, with a small but significant reduction also observed in outer pillar cells. Dieters cell microtubules also were severely disorganized and less tightly bundled in Gas2 knockout mice. Transmission electron microscopy confirmed that the number, density, and organization of pillar cell microtubules were greatly reduced in the mutant mice, and crosslinks between microtubules and actin were mostly absent. Atomic force microscopy revealed that the Gas2 knockout supporting cells were less stiff than those of wildtype mice. Analysis of distortion product otoacoustic emissions (DPOAE), a measure of outer hair cell (OHC) amplification and organ of Corti mechanics, showed a significant 10 to 20 dB reduction in mutant mice compared to controls, indicating that the reduction in supporting cell stiffness interferes with the OHC-mediated active process, resulting in hearing loss. Measurement of vibratory responses to sound in live mice revealed that mutant mice had lower gain and a reduced frequency range compared to controls, and that near the characteristic frequency (frequency of maximal vibration to lowest intensity stimuli), the traveling wave propagated more slowly in the mutant mice and there was less longitudinal coupling. The authors concluded that Gas2 mutations cause hearing loss through a mechanism that alters the way the traveling sound wave propagates along the cochlea.
In 4 brothers of Somalian ancestry with congenital nonsyndromic sensorineural deafness (DFNB125; 620877), Chen et al. (2021) identified homozygosity for a splice site mutation (c.723+1G-A, NM_005256.3) in intron 6 of the GAS2 gene. The second-cousin unaffected parents were heterozygous for the mutation, which was not found in 2 unaffected brothers or in more than 15,000 exomes in an in-house database or in the gnomAD database (v2.1.1). RT-PCR analysis on RNA isolated from EBV-transformed cells from 1 of the affected brothers, the parents, and 2 unaffected brothers showed that the mutation causes retention of intron 6, with almost no wildtype splicing observed in the affected individual. The mutant transcript was predicted to result in a premature termination codon at position c.723+67-69.
Brancolini, C., Bottega, S., Schneider, C. Gas2, a growth arrest-specific protein, is a component of the microfilament network system. J. Cell Biol. 117: 1251-1261, 1992. [PubMed: 1607387] [Full Text: https://doi.org/10.1083/jcb.117.6.1251]
Chen, T., Rohacek, A. M., Caporizzo, M., Nankali, A., Smits, J. J., Oostrik, J., Lanting, C. P., Kucuk, E., Gilissen, C., van de Kamp, J. M., Pennings, R. J. E., Rakowiecki, S. M., Kaestner, K. H., Ohlemiller, K. K., Oghalai, J. S., Kremer, H., Prosser, B. L., Epstein, D. J. Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing. Dev. Cell 56: 1526-1540, 2021. [PubMed: 33964205] [Full Text: https://doi.org/10.1016/j.devcel.2021.04.017]
Collavin, L., Buzzai, M., Saccone, S., Bernard, L., Federico, C., DellaValle, G., Brancolini, C., Schneider, C. cDNA characterization and chromosome mapping of the human GAS2 gene. Genomics 48: 265-269, 1998. [PubMed: 9521882] [Full Text: https://doi.org/10.1006/geno.1997.5172]
Colombo, M. P., Martinotti, A., Howard, T. A., Schneider, C., D'Eustachio, P., Seldin, M. F. Localization of growth arrest-specific genes on mouse chromosomes 1, 7, 8, 11, 13, and 16. Mammalian Genome 2: 130-134, 1992. [PubMed: 1347472] [Full Text: https://doi.org/10.1007/BF00353861]
Schneider, C., King, R. M., Philipson, L. Genes specifically expressed at growth arrest of mammalian cells. Cell 54: 787-793, 1988. [PubMed: 3409319] [Full Text: https://doi.org/10.1016/s0092-8674(88)91065-3]