Alternative titles; symbols
HGNC Approved Gene Symbol: GOSR2
SNOMEDCT: 783062001;
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38) : 17:46,923,160-46,975,890 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.32 | Epilepsy, progressive myoclonic 6 | 614018 | Autosomal recessive | 3 |
| Muscular dystrophy, congenital, with or without seizures | 620166 | Autosomal recessive | 3 |
The GOSR2 gene encodes a member of the soluble NSF attachment protein receptor (SNARE) family of vesicle docking proteins (Hay et al., 1997). GOSR2 localizes to the Golgi apparatus and mediates docking and fusion of vesicles originating from the endoplasmic reticulum (ER), consistent with a role in vesicular trafficking (summary by Larson et al., 2018).
Hay et al. (1997) isolated rat Gosr2, which they called membrin, from a rat liver protein complex. The authors called the 25-kD protein 'membrin' to show its membership in a large complex of related proteins and to emphasize its probable importance to the trafficking of intracellular membranes.
Lowe et al. (1997) identified cDNAs encoding human, mouse, and rat membrin, which they named GS27 (Golgi SNARE, 27-kD). Immunofluorescence of mammalian cells revealed that endogenous GS27 was associated with the Golgi apparatus and its surrounding vesicular structures. Using an in vitro transport assay, the authors demonstrated that GS27 participated in protein movement from the medial- to trans-Golgi and the trans-Golgi network, but unlike GS28 (GOSR1; 604026), GS27 had no effect on transport from the ER to the cis/medial-Golgi. They concluded that protein movement through the Golgi apparatus depends on SNARE-mediated vesicular transport.
By analysis of radiation hybrids and by fluorescence in situ hybridization, Bui et al. (1999) mapped the GOSR2 gene to chromosome 17q21.
In eukaryotic cells, the Golgi apparatus receives newly synthesized proteins from the endoplasmic reticulum (ER) and delivers them, after covalent modification, to their destination in the cell. These proteins move from the inside (cis) face of the Golgi to the plasma-membrane (trans) side, through a stack of cisternae, towards the trans-Golgi network (TGN). The specificity of membrane transport reactions is thought to be determined by correct pairing of vesicle-associated SNAREs (v-SNAREs) with those on the target membrane (t-SNAREs) to form a complex. This complex then recruits soluble NSF attachment proteins (SNAPs) and N-ethylmaleimide-sensitive factor (NSF; 601633) to form a 20S SNARE complex. Hay et al. (1997) isolated a rat liver protein complex representing an intermediate in ER-to-Golgi transfer reactions. The complex contained the proposed cis-Golgi vesicle receptor syntaxin-5 (603189), a 28-kD Golgi-associated SNARE (GOSR1; 604026), rat homologs of the yeast Bet1 (605456) and Sly1 proteins, and 2 novel proteins, sec22b (604029) and a 25-kD membrin protein. Like GOSR1, syntaxin-5, sec22b, and rat bet1, membrin is a C terminal-anchored, cytoplasmically oriented integral membrane protein. By immunofluorescence of mammalian cells expressing epitope-tagged membrin, Hay et al. (1997) found that the expressed protein accumulated primarily at the ER in half the cells, and primarily in the Golgi in the remaining cells. Other members of the complex localized to Golgi membranes, so that the complex appeared to recapitulate vesicle docking interactions of proteins originating from distinct compartments.
Progressive Myoclonic Epilepsy 6
In 5 unrelated patients with progressive myoclonic epilepsy-6 (EPM6; 614018), Corbett et al. (2011) identified a homozygous loss-of-function mutation in the GOSR2 gene (G144W; 604027.0001). Haplotype analysis indicated a founder effect, most likely of European origin, that arose approximately 3,600 years ago.
Congenital Muscular Dystrophy with or without Seizures
In a 36-month-old boy with congenital muscular dystrophy with seizures (MYOS; 620166), Tsai et al. (2013) identified compound heterozygous mutations in the GOSR2 gene: a splice site mutation (604027.0003) and G144W (604027.0001). The mutations were found by whole-exome sequencing; functional studies of the variants were not performed.
In a 6-year-old girl (patient 3) with MYOS, Larson et al. (2018) identified compound heterozygous mutations in the GOSR2 gene (M1R, 604027.0004 and G144W). The mutations were found by whole-exome sequencing; functional studies of the variants were not performed.
In a 22-month-old girl with MYOS, Henige et al. (2021) identified compound heterozygous mutations in the GOSR2 gene: G144W and Q28X (604027.0005). The mutations, which were found by trio-based exome sequencing, were in trans and inherited from asymptomatic parents. Functional studies of the variants were not performed. The Q28X mutation was predicted to result in nonsense-mediated mRNA decay or protein truncation, causing a severe functional defect, whereas G144W most likely retained partial function. Henige et al. (2021) postulated that there may be a genotype/phenotype correlation based on residual GOSR2 protein function, with more detrimental mutations resulting in a more severe phenotype manifest as congenital muscular dystrophy.
In a 48-year-old woman with MYOS, Stemmerik et al. (2021) identified compound heterozygous mutations in the GOSR2 gene (c.204-7A-G, 604027.0006; R107X, 604027.0007). cDNA analysis in patient muscle tissue showed that 40% of the GOSR2 transcripts were abnormally spliced and that membrin protein staining was reduced in muscle tissue. Additionally, alpha-dystroglycan was hyperglycosylated. The patient had a relatively milder phenotype compared to other patients with MYOS, which Stemmerik et al. (2021) hypothesized was due to residual normal splicing of MYOS.
Associations Pending Confirmation
Meyer et al. (2020) performed a genomewide association study to investigate image-derived phenotypes of cardiac trabeculae using the fractal analysis of trabecular morphology in 18,096 participants in the UK Biobank. They identified 16 significant loci that contained genes associated with hemodynamic phenotypes and regulation of cytoskeletal arborization. For both dilated cardiomyopathy and heart failure, loci associated with decreasing trabeculation were associated with increased susceptibility to disease. The locus around GOSR2 showed strong association in 2 patient cohorts with dilated cardiomyopathy and heart failure, respectively. In both cohorts, an increase in trabeculation led to a decreased risk of disease. CRISPR-mediated gosr2 knockout medaka embryos exhibited a range of severe to moderate abnormal heart morphologic abnormalities. Meyer et al. (2020) concluded that their findings suggested a role for myocardial trabeculae in the function of the adult heart, identified conserved pathways that regulate structural complexity, and revealed the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.
For discussion of a possible association between variation in the GOSR2 gene and nonsyndromic deafness, see 604027.0008.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human GOSR2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Progressive Myoclonic Epilepsy-6
In 5 unrelated patients with progressive myoclonic epilepsy-6 (EPM6; 614018), Corbett et al. (2011) identified a homozygous c.430G-T transversion (c.430G-T, NM_004287.3) in the GOSR2 gene, resulting in a gly144-to-trp (G144W) substitution in a conserved residue in the Qb-SNARE domain. The mutation was not found in 584 control chromosomes. Studies of patient fibroblasts showed that the mutant protein failed to localize to the Golgi, and the mutant protein could not rescue growth of a yeast strain lacking the Gosr2 ortholog. These findings indicated a loss-of-function effect. Haplotype analysis indicated a founder effect, most likely of European origin, that arose approximately 3,600 years ago. The patients presented in the first years of life with ataxia, followed by action myoclonus, seizures, scoliosis, and loss of independent ambulation in the second decade.
Van Egmond et al. (2014) reported 5 additional Dutch patients with EPM6, all of whom were homozygous for the G144W mutation. The phenotype was homogeneous and similar to that reported by Corbett et al. (2011).
Congenital Muscular Dystrophy with or without Seizures
For discussion of the G144W mutation in the GOSR2 gene that was found in compound heterozygous state in a patient with congenital muscular dystrophy with seizures (MYOS; 620166) by Tsai et al. (2013), see 604027.0003.
For discussion of the G144W mutation in the GOSR2 gene that was found in compound heterozygous state in a patient with MYOS by Larson et al. (2018), see 604027.0004. Larson et al. (2018) stated that G144W was found in 5 of 121,408 alleles in the ExAC database with no homozygous individuals.
For discussion of the G144W mutation in the GOSR2 gene that was found in compound heterozygous state in a patient with MYOS by Henige et al. (2021), see 604027.0005.
In a 61-year-old woman with progressive myoclonic epilepsy-6 (EPM6; 614018), Praschberger et al. (2015) identified compound heterozygous mutations in the GOSR2 gene: an in-frame 3-bp deletion (c.491_493delAGA), resulting in the deletion of the highly conserved residue Lys164 (K164del) in the SNARE domain of the protein, and the common G144W mutation (604027.0001). The patient's brother, who had cervical dystonia, was heterozygous for the G144W mutation. Functional studies of the mutations were not performed. The patient was 1 of 43 patients with a similar disorder who were screened for defects in the GOSR2 gene.
In a 36-month-old boy with congenital muscular dystrophy with seizures (MYOS; 620166), Tsai et al. (2013) identified compound heterozygous mutations in the GOSR2 gene: a splice site mutation (c.336+1G-A) and G144W (604027.0001). The mutations were found by whole-exome sequencing; functional studies of the variants were not performed.
In a 6-year-old girl (patient 3) with congenital muscular dystrophy with seizures (MYOS; 620166), Larson et al. (2018) identified compound heterozygous mutations in the GOSR2 gene: a c.2T-G transversion (c.2T-G, NM_001012511), predicted to alter the start codon and be pathogenic, and G144W (604027.0001). The mutations were found by whole-exome sequencing. She had a similarly affected sister who died of respiratory failure at age 5 years; DNA from the sister was not available. The c.2T-G variant was present in 1 of 18,808 alleles in the ExAC database, whereas G144W was found in 5 of 121,408 alleles with no homozygous individuals. Functional studies of the variants were not performed. Skeletal muscle biopsy of patient 3 showed an active dystrophic process with hypoglycosylation of alpha-dystroglycan (DAG1; 128239) detected by Western blot analysis and immunofluorescent studies. Glycosylation of alpha-dystroglycan was normal and membrane trafficking assay kinetics involving the Golgi were similar to controls in patient fibroblasts. Both sisters developed seizures around 2 years of age; the seizures were often intractable in patient 3.
Henige et al. (2021) stated that the c.2T-G mutation would result in a met1-to-arg (M1R) substitution.
In a 22-month-old girl with congenital muscular dystrophy without clinical seizures (MYOS; 620166), Henige et al. (2021) identified compound heterozygous mutations in the GOSR2 gene: a c.82C-T transition (c.82C-T, NM_004287.3), resulting in gln28-to-ter (Q28X) substitution, and G144W (604027.0001). The mutations, which were found by trio-based exome sequencing, were in trans and inherited from asymptomatic parents. The c.82C-T transition was predicted to result in nonsense-mediated mRNA decay or protein truncation, resulting in a severe functional defect. However, functional studies of the variants were not performed. The patient had profound developmental delays, required a feeding tube, and showed EEG evidence of epileptiform activity in the absence of clinical seizures. Muscle biopsy was not performed.
In a 48-year-old woman with congenital muscular dystrophy with seizures (MYOS; 620166), Stemmerik et al. (2021) identified compound heterozygous mutations in the GOSR2 gene: a c.204-7A-G transition (c.204-7A-G, NM_004287.4), leading to abnormal splicing, and a c.319C-T transition, resulting in an arg107-to-ter (R107X; 604027.0007) substitution. The mutations, which were identified by next-generation sequencing of a panel of 256 genes and confirmed by Sanger sequencing, were identified in the carrier state in the parents. Both variants were reported in the gnomAD database at a low frequency. cDNA analysis in patient muscle tissue indicated that 40% of the GOSR2 transcripts were abnormally spliced, and membrin protein staining was reduced in muscle tissue.
For discussion of the c.319C-T transition (c.319C-T, NM_004287.4) in the GOSR2 gene, resulting in an arg107-to-ter (R107X) substitution, that was identified in compound heterozygous state in a patient with congenital muscular dystrophy with seizures (MYOS; 620166) by Stemmerik et al. (2021), see 604027.0006.
This variant is classified as a variant of unknown significance because its contribution to nonsyndromic deafness (see 220290) has not been confirmed.
In 3 sibs and a male cousin with congenital nonsyndromic profound hearing loss from an extended consanguineous Palestinian family (CJ), Aburayyan et al. (2023) identified homozygosity for a c.1A-C transversion (c.1A-C, NM_054022) in the GOSR2 gene, resulting in a met1-to-leu (M1L) substitution at the translation start codon. The mutation segregated fully with disease in the family and was not found in approximately 2,000 controls of Palestinian ancestry; the variant was present once in the gnomAD database, in heterozygous state. Western blot of lymphoblast cell lines (LCLs) from 2 of the affected individuals revealed that GOSR2 protein was detectable but significantly reduced, to 8.5% and 3.4% of control levels. Analysis of Golgi function in LCLs from patients and controls did not show any significant differences between the mutant and wildtype GOSR2, in terms of total protein secretion or GOSR2 localization. Flow cytometry assay showed significantly reduced translation of the mutant, with the GOSR2 M1L plasmid having 18% of the signal of wildtype plasmid; Western blot of transfected cells confirmed that M1L was 18% of wildtype protein levels. The authors noted that it was unclear why these affected individuals did not show the severe neurologic features that had been reported previously in patients with biallelic mutations in the GOSR2 gene, or conversely, why those patients with GOSR2-associated neurologic conditions had apparently normal hearing.
Aburayyan, A., Carlson, R. J., Rabie, G. N., Lee, M. K., Gulsuner, S., Walsh, T., Avraham, K. B., Kanaan, M. N., King, M.-C. A paradoxical genotype-phenotype relationship: Low level of GOSR2 translation from a non-AUG start codon in a family with profound hearing loss. Hum. Molec. Genet. 32: 2265-2268, 2023. [PubMed: 37074134] [Full Text: https://doi.org/10.1093/hmg/ddad066]
Bui, T. D., Levy, E. R., Subramaniam, V. N., Lowe, S. L., Hong, W. cDNA characterization and chromosomal mapping of human Golgi SNARE GS27 and GS28 to chromosome 17. Genomics 57: 285-288, 1999. [PubMed: 10198168] [Full Text: https://doi.org/10.1006/geno.1998.5649]
Corbett, M. A., Schwake, M., Bahlo, M., Dibbens, L. M., Lin, M., Gandolfo, L. C., Vears, D. F., O'Sullivan, J. D., Robertson, T., Bayly, M. A., Gardner, A. E., Vlaar, A. M., Korenke, G. C., Bloem, B. R., de Coo, I. F., Verhagen, J. M. A., Lehesjoki, A.-E., Gecz, J., Berkovic, S. F. A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia. Am. J. Hum. Genet. 88: 657-663, 2011. [PubMed: 21549339] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.011]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Hay, J. C., Chao, D. S., Kuo, C. S., Scheller, R. H. Protein interactions regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells. Cell 89: 149-158, 1997. [PubMed: 9094723] [Full Text: https://doi.org/10.1016/s0092-8674(00)80191-9]
Henige, H., Kaur, S., Pappas, K. Compound heterozygous variants in GOSR2 associated with congenital muscular dystrophy: a case report. Europ. J. Med. Genet. 64: 104184, 2021. [PubMed: 33639315] [Full Text: https://doi.org/10.1016/j.ejmg.2021.104184]
Larson, A. A., Baker, P. R., II, Milev, M. P., Press, C. A., Sokol, R. J., Cox, M. O., Lekostaj, J. K., Stence, A. A., Bossler, A. D., Mueller, J. M., Prematilake, K., Tadjo, T. F., Williams, C. A., Sacher, M., Moore, S. A. TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of alpha-dystroglycan and muscular dystrophy. Skeletal Muscle 8: 17, 2018. [PubMed: 29855340] [Full Text: https://doi.org/10.1186/s13395-018-0163-0]
Lowe, S. L., Peter, F., Subramaniam, V. N., Wong, S. H., Hong, W. A SNARE involved in protein transport through the Golgi apparatus. Nature 389: 881-884, 1997. [PubMed: 9349823] [Full Text: https://doi.org/10.1038/39923]
Meyer, H. V., Dawes, T. J. W., Serrani, M., Bai, W., Tokarczuk, P., Cai, J., de Marvao, A., Henry, A., Lumbers, R. T., Gierten, J., Thumberger, T., Wittbrodt, J., Ware, J. S., Rueckert, D., Matthews, P. M., Prasad, S. K., Costantino, M. L., Cook, S. A., Birney, E., O'Regan, D. P. Genetic and functional insights into the fractal structure of the heart. Nature 584: 589-594, 2020. [PubMed: 32814899] [Full Text: https://doi.org/10.1038/s41586-020-2635-8]
Praschberger, R., Balint, B., Mencacci, N. E., Hersheson, J., Rubio-Agusti, I., Kullmann, D. M., Bettencourt, C., Bhatia, K., Houlden, H. Expanding the phenotype and genetic defects associated with the GOSR2 gene. Mov. Disord. Clin. Pract. 2: 271-273, 2015. [PubMed: 30363482] [Full Text: https://doi.org/10.1002/mdc3.12190]
Stemmerik, M. G., Borch, J. S., Duno, M., Krag, T., Vissing, J. Myopathy can be a key phenotype of membrin (GOSR2) deficiency. Hum. Mutat. 42: 1101-1106, 2021. [PubMed: 34167170] [Full Text: https://doi.org/10.1002/humu.24247]
Tsai, L., Schwake, M., Corbett, M. A., Gecz, J., Berkovic, Shieh, P. B. GOSR 2: a novel form of congenital muscular dystrophy. (Abstract) Neuromusc. Disord. 23: 748 only, 2013.
van Egmond, M. E., Verschuuren-Bemelmans, C. C., Nibbeling, E. A., Elting, J. W. J., Sival, D. A., Brouwer, O. F., de Vries, J. J., Kremer, H. P., Sinke, R. J., Tijssen, M. A., de Koning, T. J. Ramsay Hunt syndrome: clinical characterization of progressive myoclonus ataxia caused by GOSR2 mutation. Mov. Disord. 29: 139-143, 2014. [PubMed: 24458321] [Full Text: https://doi.org/10.1002/mds.25704]