HGNC Approved Gene Symbol: GNB2
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38): 7:100,673,740-100,679,169 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.1 | ?Sick sinus syndrome 4 | 619464 | Autosomal dominant | 3 |
| Neurodevelopmental disorder with hypotonia and dysmorphic facies | 619503 | Autosomal dominant | 3 |
Heterotrimeric G proteins, made up of an alpha subunit (see GNAS, 139320), a beta subunit, like GNB2 (see also GNB1; 139380), 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 (summary by Rosskopf et al., 2003). Beta subunits in general are the primary mediators of direct G protein-protein interactions to initiate downstream intracellular signaling cascades (summary by Lansdon et al., 2021).
Gao et al. (1987) isolated a cDNA that encodes a second form of the beta-subunit of signal-transducing guanine nucleotide-binding regulatory proteins (G proteins). The cDNA corresponded to a 1.8-kb mRNA, and nucleotide sequence analysis indicated that the encoded polypeptide consists of 340 amino acid residues with a molecular weight of 37,335. Although the deduced polypeptide was found to be of the same size as that reported previously for the beta subunit (beta-1), 10% of the amino acid residues were different.
By qRT-PCR in various human heart tissues and human brain, Stallmeyer et al. (2017) observed expression of the GNB2 gene in all cardiac subcompartments and in the brain. Compared with the expression level in the atrium, the highest transcriptional levels were observed in the atrioventricular node and brain. Because heterotrimeric G proteins are composed of several alpha, beta, and gamma subunits, the authors also confirmed expression of all 5 GNB genes and 3 GNG genes in human heart compartments and the brain.
Rosskopf et al. (2003) determined that the GNB2 gene contains 10 exons. The first exon is noncoding.
Blatt et al. (1988) assigned the GNB2 gene to human chromosome 7 by hybridization of clones to DNA from somatic cell hybrids. By studying a YAC containing the EPO gene (133170), Kere et al. (1991) demonstrated that the GNB2 gene is located within 30 to 80 kb of EPO and most likely centromeric of it. GNAI1 (139310) is located in the same area.
Lovett et al. (1991) developed a strategy for the rapid enrichment and identification of cDNAs encoded by large genomic regions. The basis of this 'direct selection' scheme was the hybridization of an entire library of cDNAs to an immobilized genomic clone. The scheme was tested using a 550-kb YAC clone that contained the EPO gene. Using this clone and a fetal kidney cDNA library, they achieved a 1,000-fold enrichment of EPO cDNAs in one cycle of enrichment. An anonymous cDNA encoded by the YAC was greatly enriched and found to represent the GNB2 gene. Restriction mapping located it within 30-70 kb of the EPO gene. Parimoo et al. (1991) likewise developed a method of cDNA selection based on hybridization of cDNA fragments to immobilized DNA and recovery of the selected cDNAs by polymerase chain reaction (PCR). These methods address the recurrent problem in genome mapping and positional cloning, namely, identification of coding segments in large fragments of genomic DNA.
Peng et al. (1992) pointed out that although the alpha subunit shows great diversity and is thought to confer functional specificity to a particular G protein, the beta subunit, which is much less diverse, is believed to have no role in G protein specificity. Using immunocytochemistry, they found, however, distinct distribution patterns for different beta and gamma subunits in the retina. In particular, rod and cone photoreceptors, which both subserve phototransduction but differ in light-response properties, have different beta and gamma subunits in their outer segments. Thus, the G protein mediating phototransduction shows cell-specific forms of the beta and gamma subunits in addition to the alpha subunit. This surprising finding supported the hypothesis that these subunits contribute to functional specificity of the G protein.
Wolfe et al. (2003) demonstrated that inhibition of the alpha-1H (Ca(v)3.2) (CACNA1H; 607904), but not alpha-1G (Ca(v)3.1) (CACNA1G; 604065), low voltage-activated calcium channels is mediated selectively by G protein beta-2-gamma-2 subunits (GNB2 and GNG2) subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the alpha-1H channel is crucial for inhibition because its replacement abrogates inhibition and its transfer to nonmodulated alpha-1G channels confers beta-2-gamma-2-dependent inhibition. Beta-gamma reduces channel activity independent of voltage, a mechanism distinct from the established beta-gamma-dependent inhibition of non-L-type high voltage-activated channels of the Ca(v)2 family. Wolfe et al. (2003) concluded that their studies identified the alpha-1H channel as a new effector for G protein beta-gamma subunits, and highlight the selective signaling roles available for particular beta-gamma combinations.
Sick Sinus Syndrome 4
In a large 3-generation German family with sick sinus syndrome and atrioventricular block mapping to chromosome 7q21.1-q31.1 (SSS4; 619464), Stallmeyer et al. (2017) performed targeted exome sequencing and identified a heterozygous missense mutation in the GNB2 gene (R52L; 139390.0001) that was confirmed by Sanger sequencing to segregate fully with disease. Functional analysis revealed sustained activation of cardiac G protein-activated potassium (GIRK) channels with the R53L mutant, which the authors suggested is likely to hyperpolarize the myocellular membrane potential and reduce spontaneous activity.
Neurodevelopmental Disorder with Hypotonia and Dysmorphic Facies
In a 7.5-year-old Japanese girl with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Fukuda et al. (2020) identified a de novo heterozygous missense mutation in the GNB2 gene (G77R; 139390.0002). The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to be detrimental since mutations affecting the homologous Gly77 residue in the GNB1 gene (139380) have been reported in patients with an overlapping neurodevelopmental disorder (616973).
In a 15-year-old girl with NEDHYDF, Lansdon et al. (2021) identified a de novo heterozygous missense mutation in the GNB2 gene, resulting in a gly77-to-trp (G77W; 139390.0003) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 11 unrelated patients with NEDHYDF, Tan et al. (2022) identified 5 different de novo heterozygous missense mutations in the GNB2 gene (see, e.g., 139390.0002; 139390.0004-139390.0006). The patients were ascertained through the GeneMatcher Exchange program and the mutations were found through genome or exome sequencing. Functional studies of the variants and studies of patient cells were not performed. However, molecular modeling indicated that all of the mutations occurred at conserved residues at different parts of shared interface regions of GNB2, particularly disrupting affinity to the G-alpha subunit. The mutations were predicted to differentially alter binding to various effectors as well, which would influence downstream signaling pathways. Tan et al. (2022) suggested that the mutations may have subtle functional differences, which may account for phenotypic variability.
In 11 affected members of a 3-generation German family with sick sinus syndrome and atrioventricular block (SSS4; 619464), Stallmeyer et al. (2017) identified heterozygosity for a c.155G-T transversion (c.155G-T, NM_005273.3) in exon 4 of the GNB2 gene, resulting in an arg52-to-leu (R52L) substitution at a highly conserved residue located just before the first WD repeat motif. The mutation segregated fully with disease in the family and was not found in the Exome Variant Server or ExAC databases. Whole-cell patch-clamp analysis of transfected HEK293T cells demonstrated significantly enhanced and sustained activation of the cardiac G protein-activated potassium (GIRK) channel when the R52L mutant was coexpressed with GNG2 (606981).
In a 7.5-year-old Japanese girl with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Fukuda et al. (2020) identified a de novo heterozygous c.229G-A transition (c.229G-A, NM_005273.3) in the GNB2 gene, resulting in a gly77-to-arg (G77R) substitution at a conserved residue. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to be detrimental since mutations affecting the homologous Gly77 residue in the GNB1 gene (139380) have been reported in patients with an overlapping neurodevelopmental disorder (616973).
Tan et al. (2022) identified a de novo heterozygous G77R mutation in 4 unrelated patients (P4, P5, P6, and P7) with NEDHYDF. Functional studies of the variant were not performed.
In a 15-year-old girl with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Lansdon et al. (2021) identified a de novo heterozygous c.229G-T transversion (c.229G-T, NM_005273.4) in the GNB2 gene, resulting in a gly77-to-trp (G77W) substitution at a conserved residue. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patient also carried variants of uncertain significance in several other genes that may have contributed to the phenotype.
In 3 unrelated patients (P1, P2, and P3) with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Tan et al. (2022) identified a de novo heterozygous c.217G-A transition (c.217G-A, NM_005273.3) in the GNB2 gene, resulting in an ala73-to-thr (A73T) substitution at a conserved residue in a WD40 domain. The mutation was found by genome or exome sequencing. It was present once in the heterozygous state in the gnomAD database (3.2 x 10(-5)), and the authors suggested that the control individual may have had mild developmental delay. The patients reported by Tan et al. (2022) with the A73T mutation had a somewhat milder phenotype compared to patients with other GNB2 mutations.
In a 14-year-old boy (P8) with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Tan et al. (2022) identified a de novo heterozygous c.265A-G transition (c.265A-G, NM_005273.3) in the GNB2 gene, resulting in a lys89-to-glu (K89E) substitution at a conserved residue. The same de novo heterozygous mutation was found in an unrelated fetus (P9) with multiple congenital anomalies necessitating termination of the pregnancy. The mutation, which was found by genome or exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patients cells were not performed.
In 2 unrelated patients (P10 and P11) with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Tan et al. (2022) identified a de novo heterozygous c.266A-C transversion (c.266A-C, NM_005273.3) in the GNB2 gene, resulting in a lys89-to-thr (K89T) substitution at a conserved residue. The mutation, which was found by genome or exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
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Kere, J., Taillon-Miller, P., Lovett, M., de la Chapelle, A., Donis-Keller, H. Construction of human chromosome 7 YAC contigs around the COL1A2 and EPO genes and mapping of the GNB2 gene. (Abstract) Cytogenet. Cell Genet. 58: 1922-1923, 1991.
Lansdon, L. A., Fleming, E. A., del Viso, F., Sullivan, B. R., Saunders, C. J. Second patient with GNB2-related neurodevelopmental disease: further evidence for a gene-disease association. Europ. J. Med. Genet. 64: 104243, 2021. [PubMed: 33971351] [Full Text: https://doi.org/10.1016/j.ejmg.2021.104243]
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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]
Stallmeyer, B., Kuss, J., Kotthoff, S., Zumhagen, S., Vowinkel, K., Rinne, S., Matschke, L. A., Friedrich, C., Schulze-Bahr, E., Rust, S., Seebohm, G., Decher, N., Schulze-Bahr, E. A mutation in the G-protein gene GNB2 causes familial sinus node and atrioventricular conduction dysfunction. Circ. Res. 120: e33-e44, 2017. [PubMed: 28219978] [Full Text: https://doi.org/10.1161/CIRCRESAHA.116.310112]
Tan, N. B., Pagnamenta, A. T., Ferla, M. P., Gadian, J., Chung, B. H. Y., Chan, M. C. Y., Fung, J. L. F., Cook, E., Guter, S., Boschann, F., Heinen, A., Schallner, J., and 26 others. Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability. J. Med. Genet. 59: 511-516, 2022. [PubMed: 34183358] [Full Text: https://doi.org/10.1136/jmedgenet-2020-107462]
Wolfe, J. T., Wang, H., Howard, J., Garrison, J. C., Barrett, P. Q. T-type calcium channel regulation by specific G-protein beta-gamma subunits. Nature 424: 209-213, 2003. [PubMed: 12853961] [Full Text: https://doi.org/10.1038/nature01772]