Alternative titles; symbols
HGNC Approved Gene Symbol: GNB1
Cytogenetic location: 1p36.33 Genomic coordinates (GRCh38) : 1:1,785,286-1,891,087 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.33 | Intellectual developmental disorder, autosomal dominant 42 | 616973 | Autosomal dominant | 3 |
| Leukemia, acute lymphoblastic, somatic | 613065 | 3 | ||
| Myelodysplastic syndrome, somatic | 614286 | 3 |
Heterotrimeric guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. Each subunit of the G protein complex is encoded by a member of 1 of 3 corresponding gene families, alpha, beta, and gamma (Hurowitz et al., 2000).
Retinal transducin is a guanine nucleotide regulatory protein that activates a cGMP phosphodiesterase in photoreceptor cells. Fong et al. (1986) identified and analyzed cDNA clones of the bovine transducin beta subunit and deduced the primary structure of a 340-amino acid protein. Significant homology was found with the yeast CDC4 gene product. The beta-subunit polypeptide, of relative molecular mass 37,375 Da, is encoded by a 2.9-kb mRNA. All mammalian tissues and clonal cell lines examined contained at least 2 beta-related mRNAs, usually 1.8 and 2.9 kb long. The authors suggested that there may be a diversity of beta subunit-related mRNAs that could encode different proteins.
Codina et al. (1986) cloned a full-length G protein beta-1 subunit (GNB1) from a human liver cDNA library. They found that the deduced 340-amino acid protein is identical to that encoded by bovine retinal rod cell cDNA of the beta subunit of transducin.
Using coprecipitation analysis, Rosskopf et al. (2003) showed that GNB1 formed dimers with all gamma subunits analyzed. The strength of the interaction was variable and was strongest between GNB1 and GNG3 (608941), GNG10 (604389), GNG12, and GNG13 (607298).
Using immunoprecipitation, Murakami et al. (2019) showed that Gnb1 interacted with the pyrin (608107) domain (PYD) of Nlrp3 (606416) following Nlrp3 activation in mouse bone marrow-derived macrophages. Through its interaction with Nlrp3, Gnb1 negatively regulated Nlrp3 inflammasome activation by suppressing Asc (PYCARD; 606838) oligomerization induced by Nlrp3.
Rosskopf et al. (2003) determined that the GNB1 gene has 12 exons. The first 2 exons and the last exon are noncoding.
Using a cDNA probe against a mouse/human somatic cell hybrid panel, Sparkes et al. (1987) mapped the human beta-1 polypeptide of G protein to human chromosome 1. Levine et al. (1990) confirmed the assignment to chromosome 1 by Southern analysis of somatic cell hybrids, and Levine et al. (1990) and Modi et al. (1991) regionalized the assignment to 1pter-p31.2 by in situ hybridization.
Danciger et al. (1990) mapped the mouse Gnb1 to distal chromosome 4.
Intellectual Developmental Disorder 42, Autosomal Dominant
In 13 unrelated patients with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified 9 different de novo heterozygous missense mutations in the GNB1 gene (see, e.g., 139380.0001-139380.0005). The mutations were identified by exome sequencing and confirmed by Sanger sequencing. The patients were ascertained from a cohort of 5,855 individuals with a presumed genetic disorder of unknown cause. Functional studies and studies of patient cells were not performed by Petrovski et al. (2016). However, Petrovski et al. (2016) noted that Yoda et al. (2015) had identified somatic mutations in the GNB1 gene that were associated with hematologic transformation. Functional studies of 3 of the mutations (D76G, 139380.0001; I80T, 139380.0002; I80N, 139380.0003) that were also identified as germline mutations in the patients reported by Petrovski et al. (2016) had reduced binding to almost all G-alpha subunits and/or conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface. The mutations resulted in activation of the PI3K-AKT-mTOR and MAPK pathways, consistent with a gain of function.
In 16 patients with MRD42, Lohmann et al. (2017) identified 14 mutations in the GNB1 gene, including 2 frameshift (139380.0007 and 139380.0008), 2 splicing (139380.0006 and 139380.0009), and 10 missense (see, e.g., 139380.0010). The mutations were identified by whole-exome sequencing; 1 mutation was inherited from a parent, 10 were de novo, and the inheritance of 3 mutations could not be determined due to lack of parental samples. Using a cell-based bioluminescence resonance energy transfer (BRET) assay, Lohmann et al. (2017) demonstrated that 7 of the missense mutations resulted in deficits in receptor-driven G protein activation.
Hemati et al. (2018) reported 18 patients with MRD42 and de novo heterozygous mutations in the GNB1 gene. Twelve patients had heterozygosity for previously identified mutations, including 8 patients with I80T (139380.0002). One of the mutations (C114Y; 139380.0011) was identified in a somatic mosaic state. All of the mutations were found by trio whole-exome sequencing.
In a 4-year-old girl with MRD42, Szczaluba et al. (2018) identified a de novo heterozygous missense mutation (G77V; 139380.0012) in the GNB1 gene. The mutation was found by trio whole-exome sequencing and confirmed by Sanger sequencing.
Somatic Mutations in Cancer
Yoda et al. (2015) identified heterozygous somatic mutations in the GNB1 gene (see, e.g., D76G, 139380.0001; I80T, 139380.0002; I80N, 139380.0003) and GNB2 (139390) genes in tumor tissue derived from patients with various malignancies, both solid tumors and hematologic malignancies, including acute lymphoblastic leukemia (ALL; 613065), myelodysplastic syndrome (MDS; 614286), and chronic lymphocytic leukemia (CLL; 151400). In vitro and in vivo functional studies showed that all of the mutations resulted in cytokine-independent growth and activation of canonical G protein signaling. Recurrent mutations affecting residues K57, K78, I80, K89, and M101 were located on the G-beta protein surface that interacts with G-alpha subunits and downstream effectors. In vitro studies showed that most mutant proteins had reduced binding to G-alpha subunits with subsequent activation of the PI3K-AKT-mTOR and MAPK signaling pathways. Eleven mutations that affected residue K57 were found in myeloid neoplasms, whereas 7 of 8 mutations affecting residue I80 were found in B-cell neoplasms. Transfection of several of the mutations into murine bone marrow resulted in the development of hematologic neoplasms, and pharmacologic inhibition of the PI3K-mTOR signaling pathway resulted in increased survival. However, in some tumors, GNB1 mutations co-occurred with oncogenic kinase alterations, such as changes in JAK2 (147796) or BRAF (164757), which conferred inhibitor resistance.
In the Rd4/+ mouse, autosomal dominant retinal degeneration cosegregates with a large inversion spanning nearly all of chromosome 4 (Roderick et al., 1997). To identify the responsible gene for this phenotype, Kitamura et al. (2006) focused on the distal breakpoint and found that it lay in the second intron of the Gnb1 gene, coding for the transducin-beta-1 protein, which is directly involved in phototransduction and in the normal maintenance of photoreceptors. Kitamura et al. (2006) determined that before the beginning of retinal degeneration in the Rd4/+ retina, the levels of Gnb1 mRNA and transducin-beta-1 were 50% of those in wildtype retina. Kitamura et al. (2006) suggested that disruption of the Gnb1 gene is responsible for Rd4/+ retinal disease.
In an 8.5-year-old boy of Ashkenazi Jewish descent with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified a de novo heterozygous c.227A-G transition (c.227A-G, NM_002074.4) in exon 6 of the GNB1 gene, resulting in an asp76-to-gly (D76G) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project (March 2013) or ExAC databases (January 2015), or in 4,326 control individuals. Functional studies of the variant and studies of patient cells were not performed. Yoda et al. (2015) had identified a somatic D76G mutation in association with acute lymphoblastic T-cell leukemia (ALL; 613065). D76G conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface.
In 3 unrelated patients with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified a de novo heterozygous c.239T-C transition (c.239T-C, NM_002074.4) in exon 6 of the GNB1 gene, resulting in an ile80-to-thr (I80T) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the Exome Sequencing Project (March 2013) and ExAC (January 2015) databases. The substitution occurs along the GNB1 protein surface that interacts with G-alpha subunits and downstream effectors. Yoda et al. (2015) had identified somatic I80T variants in association with hematologic transformation, including myelodysplastic syndrome (MDS; 614286) and chronic lymphocytic leukemia (CLL; 151400). I80T was demonstrated to have reduced binding to almost all G-alpha subunits, which conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface. Petrovski et al. (2016) noted that I80T has been reported in the ExAC browser as a low-confidence variant, but suggested that it may be a technical artifact or a postzygotic mutation. Functional studies of the variant and studies of patient cells were not performed by Petrovski et al. (2016). See 139380.0003 for another mutation affecting this residue.
Hemati et al. (2018) identified de novo heterozygosity for the I80T mutation in the GNB1 gene in 8 patients with MRD42.
In 2 unrelated patients with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified a de novo heterozygous c.239T-A transversion (c.239T-A, NM_002074.4) in exon 6 of the GNB1 gene, resulting in an ile80-to-asn (I80N) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project (March 2013) or ExAC (January 2015) databases, or in 4,326 control individuals. The substitution occurs along the GNB1 protein surface that interacts with G-alpha subunits and downstream effectors. Yoda et al. (2015) had identified somatic I80N variants in association with hematologic transformation, including acute lymphoblastic leukemia (ALL; 613065). I80N was demonstrated to have reduced binding to almost all G-alpha subunits, which conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface. Functional studies of the variant and studies of patient cells were not performed by Petrovski et al. (2016). See 139380.0002 for another mutation affecting this residue.
In a 13-month-old boy with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified a de novo heterozygous c.233A-G transition (c.233A-G, NM_002074.4) in exon 6 of the GNB1 gene, resulting in a lys78-to-arg (K78R) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project (March 2013) or ExAC (January 2015) databases, or in 4,326 control individuals. Functional studies of the variant and studies of patient cells were not performed.
In 2 unrelated patients with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Petrovski et al. (2016) identified a de novo heterozygous c.301A-G transition (c.301A-G, NM_002074.4) in exon 7 of the GNB1 gene, resulting in a met101-to-val (M101V) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP, Exome Sequencing Project (March 2013), ExAC (January 2015), and 1000 Genome Project databases. Functional studies of the variant and studies of patient cells were not performed.
In a 2-year-old Saudi Arabian boy with autosomal dominant intellectual development disorder-42 (MRD42; 616973), Lohmann et al. (2017) identified a de novo heterozygous c.268-1G-T transversion (c.268-1G-T, NM_002074) in intron 6 of the GNB1 gene, predicted to cause a splicing abnormality. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or in an in-house database of 4,361 exomes. Functional studies were not performed.
In a 5-year-old Israeli boy with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Lohmann et al. (2017) identified a de novo heterozygous 4-bp deletion (c.272_275del, NM_002074) in exon 7 of the GNB1 gene, predicted to cause a frameshift. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or in an in-house database of 4,361 exomes. Functional studies were not performed.
In an 8-year-old Saudi Arabian patient with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Lohmann et al. (2017) identified a de novo heterozygous 2-bp deletion (c.915_916del, NM_002074) in exon 10 of the GNB1 gene, predicted to cause a frameshift. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or in an in-house database of 4,361 exomes. Functional studies were not performed.
In a 6-year-old Indian girl with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Lohmann et al. (2017) identified a de novo heterozygous c.917-1G-T transversion (c.917-1G-T, NM_002074) in intron 10 of the GNB1 gene, predicted to cause a splicing abnormality. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or in an in-house database of 4,361 exomes. Functional studies were not performed.
In 3 probands of Israeli, Indian, and Mexican ethnicity with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Lohmann et al. (2017) identified de novo heterozygosity for the same c.287G-T transversion (c.287G-T, NM_002074) in the GNB1 gene, resulting in an arg96-to-leu (R96L) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database or in an in-house database of 4,361 exomes. Functional studies were not performed.
In a 7-year-old Hispanic girl (patient 3) with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Hemati et al. (2018) identified mosaicism for a c.341G-A transition (c.341G-A, NM_002074.4) in the GNB1 gene, resulting in a cys114-to-tyr (C114Y) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was identified in the patient in 29 of 163 reads, representing an 18% allelic fraction. Functional studies were not performed. The patient had a relatively milder phenotype compared to other patients with MRD42, which Hemati et al. (2018) attributed to the mosaic state of the C114Y mutation.
In a 4-year-old patient with autosomal dominant intellectual developmental disorder-42 (MRD42; 616973), Szczaluba et al. (2018) identified heterozygosity for a c.230G-T transversion (c.230G-T, NM_001282539.1) in exon 6 of the GNB1 gene, resulting in a gly77-to-val (G77V) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not identified in her parents. Functional studies were not performed.
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Lohmann, K., Masuho, I., Patil, D. N., Baumann, H., Hebert, E., Steinrucke, S., Trujillano, D., Skamangas, N. K., Dobricic, V., Huning, I., Gillessen-Kaesbach, G., Westenberger, A., Savic-Pavicevic, D., Munchau, A., Oprea, G., Klein, C., Rolfs, A., Martemyanov, K. A. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans. Hum. Molec. Genet. 26: 1078-1086, 2017. [PubMed: 28087732] [Full Text: https://doi.org/10.1093/hmg/ddx018]
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Murakami, T., Ruengsinpinya, L., Nakamura, E., Takahata, Y., Hata, K., Okae, H., Taniguchi, S., Takahashi, M., Nishimura, R. G protein subunit beta 1 negatively regulates NLRP3 inflammasome activation. J. Immun. 202: 1942-1947, 2019. [PubMed: 30777924] [Full Text: https://doi.org/10.4049/jimmunol.1801388]
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Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S.-C., Kim, S. S., Liu, H., Tivey, T., and 17 others. Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance. Nature Med. 21: 71-75, 2015. [PubMed: 25485910] [Full Text: https://doi.org/10.1038/nm.3751]