Alternative titles; symbols
HGNC Approved Gene Symbol: GNB4
SNOMEDCT: 770759001;
Cytogenetic location: 3q26.33 Genomic coordinates (GRCh38) : 3:179,396,088-179,527,798 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.33 | Charcot-Marie-Tooth disease, dominant intermediate F | 615185 | Autosomal dominant | 3 |
Heterotrimeric G proteins, made up of an alpha subunit (see GNAS, 139320), a beta subunit, like GNB4, and a gamma subunit (see GNG2, 606981), relay signals from cell surface receptors to internal effectors. The alpha subunit is a GTPase that interacts in the GDP-bound state with beta-gamma dimers (Rosskopf et al., 2003).
By searching an EST database for G-protein beta-like sequences, followed by 5-prime RACE of a human brain cDNA library, Ruiz-Velasco et al. (2002) cloned GNB4. Like other beta subunits, the deduced GNB4 protein contains 340 amino acids with 7 WD repeat motifs forming a beta-propeller structure. GNB4 shares 91% identity with GNB1 (139380) and 96% identity with mouse Gnb4. PCR analysis detected high GNB4 expression in human lung, pancreas, and placenta, moderate expression in kidney and liver, and weak expression in brain and heart.
By searching an EST database for sequences similar to mouse Gnb4, followed by PCR of human B lymphoblast and brain RNA, Rosskopf et al. (2003) cloned GNB4. PCR analysis of human, rat, and mouse tissues and cultured cells showed wide GNB4 expression.
Soong et al. (2013) found that GNB4 colocalized with neurofilament heavy chain and S100 in peripheral human nerves, indicating that it is expressed in both axons and Schwann cells.
By heterologous overexpression in rat sympathetic neurons, Ruiz-Velasco et al. (2002) found that human G-beta-4 coexpressed with G-gamma-2 (GNG2; 606981) or G-gamma-4 (GNG4; 604388) caused tonic modulation of N-type voltage-gated calcium currents and G protein-gated inwardly rectifying potassium currents. Coexpression of G-beta-4, G-gamma-2 and G-alpha-oA (GNAO1; 139311) resulted in heterotrimer formation.
Using coprecipitation analysis, Rosskopf et al. (2003) showed that GNB4 formed dimers with all 11 gamma subunits analyzed. The strength of the interaction was variable and was strongest between GNB1 and GNG4, followed by GNG13 (607298) and GNG1 (GNGT1; 189970), and was weakest with GNG8C (GNGT2; 139391). Overexpression of most GNB4-GNG dimers resulted in significant, although sometimes modest, activation of phospholipase beta-2 (PLCB2; 604114), with highest activation by the GNB4-GNG4 dimer.
Vertebrate retinas have distinct light-on (ON) and light-off (OFF) channels that originate at the level of the retinal bipolar cells. For the conversion from OFF to ON, ON bipolar cells use the GNAO1-coupled glutamate receptor-6 (GRIK2; 138244) such that binding of glutamate suppresses a cation current rather than activating it. Using immunohistochemical analysis and single-cell PCR, Huang et al. (2003) showed that the gamma subunit Gng13 (607298) was coexpressed with the beta subunits Gnb3 (139130) and Gnb4, but no other beta subunit, in dissociated mouse ON bipolar cells. Huang et al. (2003) hypothesized that these G protein subunits selectively participate in signal transduction in ON bipolar cells.
Soong et al. (2013) found that Gnb4 expression in rats decreased in nerve tissue distal to sciatic nerve transection and increased in nerve tissue after conditioning, suggesting that the protein plays a role in peripheral nerve regeneration.
Rosskopf et al. (2003) determined that the GNB4 gene contains 10 exons. The first exon is noncoding.
By genomic sequence analysis, Rosskopf et al. (2003) mapped the GNB4 gene to chromosome 3.
Gross (2018) mapped the GNB4 gene to chromosome 3q26.33 based on an alignment of the GNB4 sequence (GenBank AF300648) with the genomic sequence (GRCh38).
In affected members of a Han Chinese family with dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF; 615185) (Lee et al., 2010), Soong et al. (2013) identified a heterozygous mutation in the GNB4 gene (G53D; 610863.0001). The mutation was identified by exome sequencing. An unrelated Han Chinese girl with demyelinating CMT carried a different heterozygous mutation that occurred de novo (K89E; 610863.0002). The frequency of GNB4 mutations in the CMT cohort was 0.8% (2 of 251 families). The phenotype was characterized by onset around adolescence of slowly progressive distal muscle weakness and atrophy affecting the upper and lower limbs, as well as distal sensory impairment and areflexia. In the family, male mutation carriers were more severely affected than female mutation carriers. Immunofluorescence studies of patient sural nerves showed GNB4 staining of onion bulb formations in a rosette pattern. However, immunohistochemical studies showed weaker GNB4 expression in patient sural nerve biopsies compared to controls. Expression of both mutations in COS-7 cells showed that the mutant proteins had impaired bradykinin-induced G protein-coupled receptor intracellular signaling compared to the wildtype protein. The mutant proteins were stable in transfected cells, and Soong et al. (2013) postulated a dominant-negative effect. The findings indicated that GNB4-related G protein-coupled receptor signaling is important for proper functioning of peripheral nerves.
In affected members of a large 4-generation Han Chinese family with dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF; 615185), Soong et al. (2013) identified a heterozygous 158G-A transition in the GNB4 gene, resulting in a gly53-to-asp (G53D) substitution at a highly conserved residue. The mutation, which was identified by exome sequencing, segregated with the disorder in the family and was not found in several large control databases, including 1,920 ethnic control chromosomes. The phenotype was characterized by onset around adolescence of slowly progressive distal muscle weakness and atrophy affecting the upper and lower limbs, as well as distal sensory impairment. Male mutation carriers were more severely affected than female mutation carriers. Expression of the mutation in COS-7 cells showed that the mutant protein had impaired bradykinin-induced G-protein-coupled receptor intracellular signaling compared to the wildtype protein. The mutant protein was stable in transfected cells, and Soong et al. (2013) postulated a dominant-negative effect.
In a 9-year-old Han Chinese girl with dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF; 615185), Soong et al. (2013) identified a de novo heterozygous 265A-G transition in exon 5 of the GNB4 gene, resulting in a lys89-to-glu (K89E) substitution at a highly conserved residue. The mutation was not found in several large control databases, including 1,920 ethnic control chromosomes. Expression of the mutation in COS-7 cells showed that the mutant protein had impaired bradykinin-induced G-protein-coupled receptor intracellular signaling compared to the wildtype protein. The mutant protein was stable in transfected cells, and Soong et al. (2013) postulated a dominant-negative effect.
Gross, M. B. Personal Communication. Baltimore, Md. 3/9/2018.
Huang, L., Max, M., Margolskee, R. F., Su, H., Masland, R. H., Euler, T. G protein subunit G-gamma-13 is coexpressed with G-alpha-o, G-beta-3, and G-beta-4 in retinal ON bipolar cells. J. Comp. Neurol. 455: 1-10, 2003. [PubMed: 12454992] [Full Text: https://doi.org/10.1002/cne.10396]
Lee, Y.-C., Lee, T.-C., Lin, K.-P, Lin, M.-W., Chang, M.-H, Soong, B.-W. Clinical characterization and genetic analysis of a possible novel type of dominant Charcot-Marie-Tooth disease. Neuromusc. Disord. 20: 534-539, 2010. [PubMed: 20627571] [Full Text: https://doi.org/10.1016/j.nmd.2010.05.001]
Rosskopf, D., Nikula, C., Manthey, I., Joisten, M., Frey, U., Kohnen, S., Siffert, W. The human G protein beta-4 subunit: gene structure, expression, G-gamma and effector interaction. FEBS Lett. 544: 27-32, 2003. [PubMed: 12782285] [Full Text: https://doi.org/10.1016/s0014-5793(03)00441-1]
Ruiz-Velasco, V., Ikeda, S. R., Puhl, H. L. Cloning, tissue distribution, and functional expression of the human G protein beta-4-subunit. Physiol. Genomics 8: 41-50, 2002. [PubMed: 11842130] [Full Text: https://doi.org/10.1152/physiolgenomics.00085.2001]
Soong, B.-W., Huang, Y.-H., Tsai, P.-C., Huang, C.-C., Pan, H.-C., Lu, Y.-C., Chien, H.-J., Liu, T.-T., Chang, M.-H., Lin, K.-P., Tu, P.-H., Kao, L.-S., Lee, Y.-C. : Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 92: 422-430, 2013. [PubMed: 23434117] [Full Text: https://doi.org/10.1016/j.ajhg.2013.01.014]