Alternative titles; symbols
HGNC Approved Gene Symbol: GOLGA2
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:128,255,829-128,276,007 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Developmental delay with hypotonia, myopathy, and brain abnormalities | 620240 | Autosomal recessive | 3 |
The GOLGA2 protein provides a molecular link between the Golgi apparatus and the cytoskeleton and is a key regulator of the neuromuscular system (summary by Shamseldin et al., 2016, Kotecha et al., 2021).
Using serum from a systemic lupus erythematosus (SLE; 152700) patient to screen a human liver carcinoma cDNA expression library, Fritzler et al. (1993) cloned cDNAs representing 2 genes, named GOLGA2 and GOLGA3 (602581), that encode Golgi complex antigens. The protein product of GOLGA2 was designated golgin-95 based on its 95-kD molecular mass in mammalian cell extracts. It has 620 amino acids, an isoelectric point of 4.57, and a coiled-coil motif. Antibodies specific to golgin-95 showed anti-Golgi reactivity by immunofluorescence; the Golgi staining was blocked by treatment with brefeldin A (BFA), a fungal antibiotic known to affect the distribution of coatomer proteins of the Golgi complex.
By Western blot analysis, Liu et al. (2017) showed that Gm130 was widely expressed during mouse postnatal development, with high expression in brain and abundant expression in liver, pancreas, and lung.
Barr et al. (1998) determined that GOLGA2 interacts with GRASP65 (606867), a Golgi structural protein, in detergent extracts of rat liver Golgi membranes. They further determined that this complex can bind to the vesicle docking protein p115 (603344). Using in vitro translation and site-directed mutagenesis in conjunction with immunoprecipitation, Barr et al. (1998) localized the critical interacting domains to the C terminus of GOLGA2 and the PDZ-like domain of GRASP65. Interaction was also found to be critical for the correct targeting of both proteins to the Golgi apparatus.
Using overexpression and knockdown studies with cultured rat and mouse hippocampal and cortical neurons, Matsuki et al. (2010) found that a signaling pathway containing Stk25 (602255), Lkb1 (STK11; 602216), Strad (STRADA; 608626), and Gm130 promoted Golgi condensation and multiple axon outgrowth while inhibiting Golgi deployment into dendrites and dendritic growth. This signaling pathway acted in opposition to the reelin (RELN; 600514)-Dab1 (603448) pathway, which tended to inhibit Golgi condensation and axon outgrowth and favor Golgi deployment into dendrites and dendrite outgrowth.
Wong and Munro (2014) selected 10 mammalian golgins that are conserved outside of vertebrates and found on different regions of the Golgi and ectopically expressed them at the mitochondria through attachment to a mitochondrial transmembrane domain in place of their C-terminal Golgi targeting domain. The authors then used the distribution of cargo-laden vesicles originating from different locations as a readout for the golgins' tethering activity. Wong and Munro (2014) found that golgin-97 (GOLGA1; 602502), golgin-245 (GOLGA4; 602509), and GCC88 (607418) were able to capture endosome-to-Golgi cargoes; GM130 (GOLGA2) and GMAP210 (TRIP11; 604505) were able to capture endoplasmic reticulum (ER)-to-Golgi cargoes; and golgin-84 (GOLGA5; 606918), TMF1 (601126), and GMAP210 were able to capture Golgi resident proteins. Furthermore, electron microscopy yielded ultrastructural evidence for the accumulation of vesicular membranes around mitochondria decorated with specific golgins. Wong and Munro (2014) concluded that these data suggested that not only do the golgins capture vesicles, they also exhibit specificity toward vesicles of different origins: from the endosomes, from the ER, or from within the Golgi itself.
Park et al. (2018) showed that knockout of GOLGA2 induced autophagy in human liver Chang cells under both normal and autophagy-inducing conditions.
In a 10.5-month-old girl, born of consanguineous Saudi parents, with developmental delay with hypotonia, myopathy, and brain abnormalities (DEDHMB; 620240), Shamseldin et al. (2016) identified a homozygous frameshift mutation in the GOLGA2 gene (602580.0001). The mutation was found by a combination of autozygosity mapping and exome sequencing. Analysis of patient cells did not show evidence of nonsense-mediated mRNA decay, but immunoblot studies failed to identified a truncated GOLGA2 protein, indicating that the mutation is null at the protein level.
In an 11-year-old girl (patient 17-1853), born of consanguineous parents, with DEDHMB, Maddirevula et al. (2019) identified a homozygous frameshift mutation in the GOLGA2 gene (602580.0002). The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed.
In a 2-year-old girl, born of consanguineous Indian parents, with DEDHMB, Kotecha et al. (2021) identified a homozygous nonsense mutation in the GOLGA2 gene (Q751X; 602580.0003). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Shamseldin et al. (2016) found that morpholino knockdown of the golga2 gene in zebrafish resulted in skeletal muscle defects consistent with a myopathy and smaller brains compared to controls, suggesting microcephaly. Skeletal muscle was disorganized in mutant animals, and they showed impaired mobility consistent with overall muscle weakness. In addition, golga2 morphant fish died early, suggesting a crucial role for GOLGA2 function in survival. Expression of human wildtype GOLGA2 was able to rescue these defects.
Liu et al. (2017) found that Gm130 -/- mice were born at a normal mendelian ratio, but they displayed growth retardation, an ataxia phenotype characterized by motor defects, and death by postnatal day-35. Postnatal development and survival were not affected in mice lacking Gm130 specifically in either pancreas or lung. Mice with brain-specific deletion of Gm130 could breed and had normal survival relative to controls, but they displayed significant growth retardation. Growth retardation in mice lacking Gm130 specifically in brain was less than that in Gm130 -/- mice, suggesting that Gm130 has functions beyond nervous system. Like Gm130 -/- mice, mice with brain-specific deletion of Gm130 also displayed motor coordination defects. Brain architecture of conditional knockout mice did not show gross changes in forebrain or midbrain, but cerebellar size was dramatically reduced, with progressive cerebellar atrophy and Purkinje cell loss. Purkinje cell loss was also observed in Gm130 -/- mice. Analysis with cultured Purkinje cells showed that Gm130 was not required for initial Golgi polarization, but that it was essential to maintain polarized distribution of the Golgi apparatus, most likely through its association with Akap450 (AKAP9; 604001) and the centrosome. Consequently, loss of Gm130 disrupted Golgi architecture and positioning in Purkinje cells, resulting in impaired secretion and defective dendritic maintenance that led to defective neurotransmission and contributed to impaired functionality and long-term survival of Purkinje cells in cerebellum. Further analysis demonstrated that the particular sensitivity of Purkinje cells to loss of Gm130 was not due to a deficit in expression of other golgins or Grasp65 in this cell type.
Park et al. (2018) found that Golga2 -/- mice were born at 40% of the expected mendelian ratio and displayed growth retardation. Examination of Golga2 -/- tissues showed that Golga2 loss induced autophagy with Golgi disruption in liver and lung. Histologic analysis further revealed that Golga2 loss induced fibrosis in liver and lung.
In a 10.5-month-old girl, born of consanguineous Saudi parents, with developmental delay with hypotonia, myopathy, and brain abnormalities (DEDHMB; 620240), Shamseldin et al. (2016) identified a homozygous 4-bp deletion (c.1266_1269delGAGA, NM_004486.4) in exon 16 of the GOLGA2 gene, predicted to result in a frameshift and premature termination (Glu423ArgfsTer6). The mutation was found by a combination of autozygosity mapping and exome sequencing. Analysis of patient cells did not show evidence of nonsense-mediated mRNA decay, but immunoblot studies failed to identified a truncated GOLGA2 protein, indicating that the mutation is null at the protein level.
In an 11-year-old girl (patient 17-1853), born of consanguineous parents, with developmental delay with hypotonia, myopathy, and brain abnormalities (DEDHMB; 620240), Maddirevula et al. (2019) identified a homozygous 4-bp insertion (c.1594_1595insACCG, NM_004486.4) in the GOLGA2 gene, resulting in a frameshift and premature termination (Arg532HisfsTer21). The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed.
In a 2-year-old girl, born of consanguineous Indian parents, with developmental delay with hypotonia, myopathy, and brain abnormalities (DEDHMB; 620240), Kotecha et al. (2021) identified a homozygous c.2251C-T transition (c.2251C-T, NM_004486.4) in exon 4 of the GOLGA2 gene, resulting in a gln751-to-ter (Q751X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of function. The patient also carried a homozygous missense variant of uncertain significance (R210H) in the GLE1 gene (603371) that was not thought to be related to the phenotype.
Barr, F. A., Nakamura, N., Warren, G. Mapping the interaction between GRASP65 and GM130, components of a protein complex involved in the stacking of Golgi cisternae. EMBO J. 17: 3258-3268, 1998. [PubMed: 9628863] [Full Text: https://doi.org/10.1093/emboj/17.12.3258]
Fritzler, M. J., Hamel, J. C., Ochs, R. L., Chan, E. K. L. Molecular characterization of two human autoantigens: unique cDNAs encoding 95- and 160-kD proteins of a putative family in the Golgi complex. J. Exp. Med. 178: 49-62, 1993. [PubMed: 8315394] [Full Text: https://doi.org/10.1084/jem.178.1.49]
Kotecha, U., Mistri, M., Shah, N., Shah, P. S., Gupta, V. A. Bi-allelic loss of function variants in GOLGA2 are associated with a complex neurological phenotype: Report of a second family. Clin. Genet. 100: 748-751, 2021. [PubMed: 34424553] [Full Text: https://doi.org/10.1111/cge.14053]
Liu, C., Mei, M., Li, Q., Roboti, P., Pang, Q., Ying, Z., Gao, F., Lowe, M., Bao, S. Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice. Proc. Nat. Acad. Sci. 114: 346-351, 2017. [PubMed: 28028212] [Full Text: https://doi.org/10.1073/pnas.1608576114]
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Matsuki, T., Matthews, R. T., Cooper, J. A., van der Brug, M. P., Cookson, M. R., Hardy, J. A., Olson, E. C., Howell, B. W. Reelin and Stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 143: 826-836, 2010. [PubMed: 21111240] [Full Text: https://doi.org/10.1016/j.cell.2010.10.029]
Park, S., Kim, S., Kim, M. J., Hong, Y., Lee, A. Y., Lee, H., Tran, Q., Kim, M., Cho, H., Park, J., Kim, K. P., Park, J., Cho, M. H. GOLGA2 loss causes fibrosis with autophagy in the mouse lung and liver. Biochem. Biophys. Res. Commun. 495: 594-600, 2018. [PubMed: 29128360] [Full Text: https://doi.org/10.1016/j.bbrc.2017.11.049]
Shamseldin, H. E., Bennett, A. H., Alfadhel, M., Gupta, V., Alkuraya, F. S. GOLGA2, encoding a master regulator of golgi apparatus, is mutated in a patient with a neuromuscular disorder. Hum. Genet. 135: 245-251, 2016. [PubMed: 26742501] [Full Text: https://doi.org/10.1007/s00439-015-1632-8]
Wong, M., Munro, S. The specificity of vesicle traffic to the Golgi is encoded in the golgin coiled-coil proteins. Science 346: 1256898, 2014. Note: Electronic Article. [PubMed: 25359980] [Full Text: https://doi.org/10.1126/science.1256898]