Alternative titles; symbols
HGNC Approved Gene Symbol: ADD2
Cytogenetic location: 2p13.3 Genomic coordinates (GRCh38): 2:70,656,784-70,768,200 (from NCBI)
Adducin is a heterodimeric calmodulin (114180)-binding protein of the cell-membrane skeleton that is thought to play a role in assembly of the spectrin-actin (182860/102560) lattice that underlies the plasma membrane (Joshi et al., 1991).
Joshi et al. (1991) determined the sequence of cDNAs encoding the human alpha- (ADD1; 102680) and beta-adducins. The 726-amino acid predicted beta subunit is 49% identical to the alpha-adducin sequence.
Gilligan et al. (1997) described 5 ADD2 splice variants that differed predominantly in the splicing of 3-prime exons. Some isoforms encoded by these variants lack the central calmodulin-binding domain or the lysine-rich C-terminal domain of the full-length protein.
In a comprehensive assay of gene expression, Gilligan et al. (1999) showed ubiquitous expression of alpha- and gamma-adducin (ADD3; 601568), in contrast with the restricted expression of beta-adducin. Beta-adducin was expressed at high levels in brain and hematopoietic tissues (bone marrow in humans, and spleen in mice).
Tisminetzky et al. (1995) determined the genomic organization of the human beta-adducin gene and showed that it contains 13 exons spanning approximately 50 kb. The authors showed that alternative splicing results in the production of several different transcripts.
Gilligan et al. (1997) determined that the ADD2 gene contains 17 exons and spans over 100 kb. The first 2 exons are noncoding, and coding exons 3 through 6 are common to all splice variants. The promoter region lacks TATA or CAAT elements, but is GC-rich and contains several binding sites for transcription factors.
Ruediger et al. (2011) investigated how mossy fiber terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and the functional role of the rearrangements. Ruediger et al. (2011) showed that one-trial and incremental learning lead to robust, circuit-specific, long-lasting, and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the number of c-Fos (164810)-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. Ruediger et al. (2011) then showed that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibers has a critical role for the precision of the memory and the learned behavior. In the absence of mossy fiber long-term potentiation in Rab3a (179490)-null mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of Add2, c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibers. Ruediger et al. (2011) concluded that their results established a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further related plasticity and feedforward inhibition growth at hippocampal mossy fibers to the precision of hippocampus-dependent memories.
By somatic cell hybrid analysis, Joshi et al. (1991) found that the alpha and beta subunits of adducin are encoded by separate genes, the alpha gene being located on chromosome 4p16.3 and the beta gene on chromosome 2. Gilligan et al. (1995) mapped ADD2 to 2p14-p13 by fluorescence in situ hybridization.
White et al. (1995) mapped the mouse Add2 gene to chromosome 6 by haplotype analysis in interspecific backcross mice. Mapping of the human gene to chromosome 2 was confirmed by study of somatic cell hybrid panels by Southern blotting. The gene was further localized to 2pter-p11.2 by study of somatic cell hybrids containing portions of chromosome 2. Tisminetzky et al. (1995) regionally mapped ADD2 to 2p15-cen by in situ hybridization.
Lanzani et al. (2005) analyzed the ADD2 gene in 40 unrelated individuals and identified a C1797T polymorphism (rs4984) in the coding sequence, located on the alternatively spliced exon 15. The authors then genotyped 512 newly discovered and never-treated hypertensive patients (see 145500) for C1797T, but found no association between the polymorphism and ambulatory blood pressure or plasma levels of renin activity and endogenous ouabain.
To elucidate the role of adducin in vivo, Gilligan et al. (1999) created Add2-null mice by gene targeting, deleting exons 9 to 13. A 55-kD chimeric polypeptide was produced from the first 8 exons of Add2 and part of the neo cassette in spleen, but was not detected in peripheral red blood cells (RBCs) or brain. Add2-null RBCs were osmotically fragile, spherocytic, and dehydrated compared with the wildtype, resembling RBCs from patients with hereditary spherocytosis (see 182900). The lack of beta-adducin in RBCs led to decreased membrane incorporation of alpha-adducin (30% of normal) and unexpectedly promoted a 5-fold increase in gamma-adducin incorporation into the RBC membrane skeleton. This study demonstrated the importance of adducin to RBC membrane stability in vivo.
Muro et al. (2000) showed that in Add2 -/- mice, targeted disruption of the beta-adducin gene resulted in an 80% decrease of alpha-adducin and a 4-fold upregulation of gamma-adducin in erythrocytes. Elliptocytes, ovalocytes, and occasionally spherocytes were found in the blood smears of -/- mice. Mild hematologic findings were thought to be related to the amount of adducin remaining in the mutant animals (presumably alpha-gamma adducin).
The Milan hypertensive strain of rats develops a genetic form of renal hypertension that, when compared to its normotensive control, shows renal dysfunction similar to that of a subset of human patients with primary hypertension. Bianchi et al. (1994) showed that 1 point mutation in each of the 2 genes coding for adducin is associated with blood pressure level in this strain of rats. The hypertensive and normal rats differed, respectively, by the amino acids tyrosine and phenylalanine at position 316 of the alpha subunit; at the beta-adducin locus, the hypertensive strain was always homozygous for arginine at position 529, while the normal strain showed either arginine or glutamine in that position. The arg/gln heterozygotes showed lower blood pressure than any of the homozygotes. In vitro phosphorylation studies suggested that both of these amino acid substitutions occurred within protein kinase recognition sites. Analysis of an F2 generation demonstrated that Y (tyrosine) alleles segregated with a significant increment in blood pressure. This effect was modulated by the presence of the R (arginine) allele of the beta subunit. Bianchi et al. (1994) stated that, taken together, these findings strongly supported a role for adducin polymorphisms in causing variation of blood pressure in the Milan strain of rats. In the rat, the beta- and alpha-adducin genes were said to be located on chromosomes 4 and 14, respectively.
Chen et al. (2007) created double-knockout mice lacking beta-adducin and the headpiece domain of dematin (EPB49; 125305). Double-knockout pups were pale compared with wildtype pups, but otherwise they appeared grossly normal. Peripheral blood analysis showed severe hemolytic anemia with reduced number of erythrocytes/hematocrit/hemoglobin and an approximately 12-fold increase in the number of circulating reticulocytes. The presence of a variety of misshapen and fragmented erythrocytes correlated with increased osmotic fragility and reduced in vivo life span. Mutant erythrocyte membranes showed weak retention of spectrin-actin complexes, increased grain size, decreased filament number, and features consistent with the presence of large protein aggregates. Chen et al. (2007) concluded that dematin and adducin are essential for the maintenance of erythrocyte shape and membrane stability.
Bianchi, G., Tripodi, G., Casari, G., Salardi, S., Barber, B. R., Garcia, R., Leoni, P., Torielli, L., Cusi, D., Ferrandi, M., Pinna, L. A., Baralle, F. E., Ferrari, P. Two point mutations within the adducin genes are involved in blood pressure variation. Proc. Nat. Acad. Sci. 91: 3999-4003, 1994. [PubMed: 8171025] [Full Text: https://doi.org/10.1073/pnas.91.9.3999]
Chen, H., Khan, A. A., Liu, F., Gilligan, D. M., Peters, L. L., Messick, J., Haschek-Hock, W. M., Li, X., Ostafin, A. E., Chishti, A. H. Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia. J. Biol. Chem. 282: 4124-4135, 2007. [PubMed: 17142833] [Full Text: https://doi.org/10.1074/jbc.M610231200]
Gilligan, D. M., Lieman, J., Bennett, V. Assignment of the human beta-adducin gene (ADD2) to 2p13-p14 by in situ hybridization. Genomics 28: 610-612, 1995. [PubMed: 7490111] [Full Text: https://doi.org/10.1006/geno.1995.1205]
Gilligan, D. M., Lozovatsky, L., Gwynn, B., Brugnara, C., Mohandas, N., Peters, L. L. Targeted disruption of the beta adducin gene (Add2) causes red blood cell spherocytosis in mice. Proc. Nat. Acad. Sci. 96: 10717-10722, 1999. [PubMed: 10485892] [Full Text: https://doi.org/10.1073/pnas.96.19.10717]
Gilligan, D. M., Lozovatsky, L., Silberfein, A. Organization of the human beta-adducin gene (ADD2). Genomics 43: 141-148, 1997. [PubMed: 9244430] [Full Text: https://doi.org/10.1006/geno.1997.4802]
Joshi, R., Gilligan, D. M., Otto, E., McLaughlin, T., Bennett, V. Primary structure and domain organization of human alpha and beta adducin. J. Cell Biol. 115: 665-675, 1991. [PubMed: 1840603] [Full Text: https://doi.org/10.1083/jcb.115.3.665]
Lanzani, C., Citterio, L., Jankaricova, M., Sciarrone, M. T., Barlassina, C., Fattori, S., Messaggio, E., Di Serio, C., Zagato, L., Cusi, D., Hamlyn, J. M., Stella, A., Bianchi, G., Manunta, P. Role of the adducin family genes in human essential hypertension. J. Hypertens. 23: 543-549, 2005. [PubMed: 15716695] [Full Text: https://doi.org/10.1097/01.hjh.0000160210.48479.78]
Muro, A. F., Marro, M. L., Gajovic, S., Porro, F., Luzzatto, L., Baralle, F. E. Mild spherocytic hereditary elliptocytosis and altered levels of alpha- and gamma-adducins in beta-adducin-deficient mice. Blood 95: 3978-3985, 2000. [PubMed: 10845937]
Ruediger, S., Vittori, C., Bednarek, E., Genoud, C., Strata, P., Sacchetti, B., Caroni, P. Learning-related feedforward inhibitory connectivity growth required for memory precision. Nature 473: 514-518, 2011. [PubMed: 21532590] [Full Text: https://doi.org/10.1038/nature09946]
Tisminetzky, S., Devescovi, G., Tripodi, G., Muro, A., Bianchi, G., Colombi, M., Moro, L., Barlati, S., Tuteja, R., Baralle, F. E. Genomic organisation and chromosomal localisation of the gene encoding human beta adducin. Gene 167: 313-316, 1995. [PubMed: 8566798] [Full Text: https://doi.org/10.1016/0378-1119(95)00591-9]
White, R. A., Angeloni, S. V., Pasztor, L. M. Chromosomal localization of the beta-adducin gene to mouse chromosome 6 and human chromosome 2. Mammalian Genome 6: 741-743, 1995. [PubMed: 8563174] [Full Text: https://doi.org/10.1007/BF00354298]