Alternative titles; symbols
HGNC Approved Gene Symbol: ADRA2B
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38): 2:96,112,876-96,116,571 (from NCBI)
Regan et al. (1988) and Lomasney et al. (1990) cloned the ADRA2B gene. By Northern blot analysis of various rat tissues, Lomasney et al. (1990) detected expression of ADRA2B in liver and kidney. Unique pharmacology and tissue localization suggested that this was a previously unidentified subtype.
Regan et al. (1988) indicated that in addition to the platelet alpha-2-adrenergic receptor encoded by chromosome 10 (ADRA2A; 104210) and the renal form of the receptor encoded by chromosome 4 (ADRA2C; 104250), a related protein is encoded by chromosome 2. By hybridization with somatic cell hybrids, Lomasney et al. (1990) showed that the ADRA2B gene is located on chromosome 2.
Gross (2017) mapped the ADRA2B gene to chromosome 2q11.2 based on an alignment of the ADRA2B sequence (GenBank AF005900) with the genomic sequence (GRCh38).
Alpha-2-adrenergic receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. To help elucidate the individual roles of the 3 highly homologous alpha-2-adrenergic receptors (ADRA2A, ADRA2B, and ADRA2C) in this process, Hein et al. (1999) studied neurotransmitter release in mice in which the genes encoding the 3 alpha-2-adrenergic-receptor subtypes were disrupted. Hein et al. (1999) demonstrated that both the ADRA2A and ADRA2C subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. ADRA2A receptors inhibited transmitter release at high stimulation frequencies, whereas the ADRA2C subtype modulated neurotransmission at lower levels of nerve activity. Both low and high frequency regulation seemed to be physiologically important, as mice lacking both ADRA2A and ADRA2C receptor subtypes had elevated plasma noradrenaline concentrations and developed cardiac hypertrophy with decreased left ventricular contractility by 4 months of age.
Associations Pending Confirmation
By PCR-SSCP analysis, Heinonen et al. (1999) screened the entire coding sequence of the ADRA2B gene in 58 obese, nondiabetic Finns. They identified a polymorphism that led to a deletion of 3 glutamic acids from a glutamic acid repeat element (glu12, amino acids 297 to 309) present in the third intracellular loop of the receptor protein. This repeat element had been shown to be important for agonist-dependent receptor desensitization. Of 166 genotyped subjects, 47 (28%) had 2 normal (long) alleles (glu12/glu12), 90 (54%) were heterozygous (glu12/glu9), and 29 (17%) were homozygous for the short form (glu9/glu9). The basal metabolic rate, determined by indirect calorimetry and adjusted for fat-free body mass, fat mass, sex, and age, was 94 calories/day (5.6%) lower (95% confidence interval for difference, 32, 156) in subjects homozygous for the short allele than in subjects with 2 long alleles (F = 4.84; P = 0.009, by ANOVA). The authors concluded that a genetic polymorphism of the ADRA2B subtype could partly explain the variation in basal metabolic rate in an obese population and may therefore contribute to the pathogenesis of obesity.
Suzuki et al. (2003) investigated the association of the ADRA2B 3-glutamic acid deletion polymorphism (glu12, amino acids 297 to 309) with autonomic nervous system (ANS) activity in 381 young healthy Japanese male subjects by electrocardiogram R-R interval power spectral analysis. One hundred sixty-eight (44.1%) were homozygous for the long allele, 162 (42.5%) were heterozygous, and 51 (13.4%) were homozygous for the short allele. The allele frequency of the short allele was 0.35. In R-R spectral analysis of heart rate variability, homozygous carriers of the short allele had significantly greater low frequency and very low frequency than did homozygous carriers of the long allele, as well as a higher sympathetic nervous system index. These findings suggested that the ADRA2B deletion polymorphism might result in metabolic disorder by altering ANS function.
This variant, formerly titled EPILEPSY, FAMILIAL ADULT MYOCLONIC, 2 based on the report of De Fusco et al. (2014), has been reclassified based on the report of Corbett et al. (2019).
In affected members of 2 large multigenerational Italian families with familial adult myoclonic epilepsy-2 (FAME2; 607876), De Fusco et al. (2014) identified a heterozygous in-frame insertion/deletion (c.675_686del/ins), resulting in the substitution of 5 amino acids (HGGAL) with 4 new residues (QFGR) (H225_L229delinsQ225_F_G_R228). The variant, which was found by sequencing genes in the candidate region on chromosome 2p1.1-q1.2 identified by linkage analysis (Guerrini et al., 2001), segregated with the disorder in the families. It was not found in the dbSNP, Exome Variant Server, and 1000 Genomes Project databases, or in 575 unrelated controls from Tuscany. Haplotype analysis suggested a founder effect. The variant occurred in the third intracellular loop, a crucial conserved domain for receptor localization and signal transduction. In vitro functional expression assays in cells and Xenopus oocytes showed that the variant interfered with receptor binding to the scaffolding protein spinophilin (PPP1R9B; 603325) upon neurotransmitter activation, thus resulting in increased epinephrine-stimulated calcium signaling, consistent with a gain of function.
In affected members of the families with FAME2 reported by De Fusco et al. (2014) and Guerrini et al. (2001), Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene (616712.0001). The findings suggested that the ADRA2B allele is not causative.
Corbett, M. A., Kroes, T., Veneziano, L., Bennett, M. F., Florian, R., Schneider, A. L., Coppola, A., Licchetta, L., Franceschetti, S., Suppa, A., Wenger, A., Mei, D., and 57 others. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nature Commun. 10: 4920, 2019. Note: Electronic Article. [PubMed: 31664034] [Full Text: https://doi.org/10.1038/s41467-019-12671-y]
De Fusco, M., Vago, R., Striano, P., Di Bonaventura, C., Zara, F., Mei, D., Kim, M. S., Muallem, S., Chen, Y., Wang, Q., Guerrini, R., Casari, G. The alpha-2B-adrenergic receptor is mutant in cortical myoclonus and epilepsy. Ann. Neurol. 75: 77-87, 2014. [PubMed: 24114805] [Full Text: https://doi.org/10.1002/ana.24028]
Gross, M. B. Personal Communication. Baltimore, Md. 8/8/2017.
Guerrini, R., Bonanni, P., Patrignani, A., Brown, P., Parmeggiani, L., Grosse, P., Brovedani, P., Moro, F., Aridon, P., Carrozzo, R., Casari, G. Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures: a newly recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2. Brain 124: 2459-2475, 2001. [PubMed: 11701600] [Full Text: https://doi.org/10.1093/brain/124.12.2459]
Hein, L., Altman, J. D., Kobilka, B. K. Two functionally distinct alpha-2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402: 181-184, 1999. [PubMed: 10647009] [Full Text: https://doi.org/10.1038/46040]
Heinonen, P., Koulu, M., Pesonen, U., Karvonen, M. K., Rissanen, A., Laakso, M., Valve, R., Uusitupa, M., Scheinin, M. Identification of a three-amino acid deletion in the alpha-2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects. J. Clin. Endocr. Metab. 84: 2429-2433, 1999. [PubMed: 10404816] [Full Text: https://doi.org/10.1210/jcem.84.7.5818]
Lomasney, J. W., Lorenz, W., Allen, L. F., King, K., Regan, J. W., Yang-Feng, T. L., Caron, M. G., Lefkowitz, R. J. Expansion of the alpha-2-adrenergic receptor family: cloning and characterization of a human alpha-2-adrenergic receptor subtype, the gene for which is located on chromosome 2. Proc. Nat. Acad. Sci. 87: 5094-5098, 1990. [PubMed: 2164221] [Full Text: https://doi.org/10.1073/pnas.87.13.5094]
Regan, J. W., Kobilka, T. S., Yang-Feng, T. L., Caron, M. G., Lefkowitz, R. J., Kobilka, B. K. Cloning and expression of a human kidney cDNA for an alpha-2-adrenergic receptor subtype. Proc. Nat. Acad. Sci. 85: 6301-6305, 1988. [PubMed: 2842764] [Full Text: https://doi.org/10.1073/pnas.85.17.6301]
Suzuki, N., Matsunaga, T., Nagasumi, K., Yamamura, T., Shihara, N., Moritani, T., Ue, H., Fukushima, M., Tamon, A., Seino, Y., Tsuda, K., Yasuda, K. alpha(2B)-adrenergic receptor deletion polymorphism associates with autonomic nervous system activity in young healthy Japanese. J. Clin. Endocr. Metab. 88: 1184-1187, 2003. [PubMed: 12629104] [Full Text: https://doi.org/10.1210/jc.2002-021190]