Alternative titles; symbols
HGNC Approved Gene Symbol: ADD1
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:2,843,844-2,930,062 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | {Hypertension, essential, salt-sensitive} | 145500 | Multifactorial | 3 |
Adducin is a 200-kD heterodimeric protein associated with the erythrocyte membrane skeleton, which binds to Ca(2+)/calmodulin (see 114180), promotes binding of spectrin to actin, and is a substrate for protein kinases C and A (Gardner and Bennett, 1986; Bennett et al., 1988). The name adducin comes from the Latin 'adducere,' meaning 'to bring together.'
Adducin was first purified from human erythrocytes by Gardner and Bennett (1986) and subsequently isolated from bovine brain membranes (Bennett et al., 1988).
Joshi and Bennett (1990) investigated the structure and function of the separate domains of alpha adducin. Joshi et al. (1991) isolated reticulocyte cDNAs for alpha- and beta- (ADD2; 102681) adducin. The deduced alpha-adducin protein contains 737 amino acids and shares approximately 49% sequence identity with beta adducin, suggesting evolution by gene duplication. Each adducin subunit has 3 distinct domains: a 39-kD N-terminal globular protease-resistant domain, connected by a 9-kD domain to a 33-kD C-terminal protease-sensitive tail comprised almost entirely by hydrophilic amino acids. The head domains of both alpha- and beta-adducin have limited sequence similarity with the N-terminal actin-binding motif present in members of the spectrin superfamily and actin gelation proteins. The C termini of both proteins contain an identical 22-amino acid sequence showing similarity to the MARCKS protein (177061). Northern blot analysis of rat tissues, K562 erythroleukemia cells, and reticulocytes demonstrated ubiquitous expression of alpha adducin.
Goldberg et al. (1992) identified a 4-kb alpha-adducin transcript that was abundantly expressed in the caudate nucleus, the site of major neuronal loss in Huntington disease (HD; 143100). No sequence alterations specific to HD were discovered in sequencing the brain alpha-adducin cDNA from 2 HD patients and an age-matched control. Brain cDNA from both patients and controls showed 2 alternately spliced brain exons not previously described in erythrocyte cDNA.
In a comprehensive assay of gene expression, Gilligan et al. (1999) showed the ubiquitous expression of alpha- and gamma-adducin (ADD3; 601568), in contrast to the restricted expression of beta-adducin. Beta-adducin was expressed at high levels in brain and hematopoietic tissues (bone marrow in humans, spleen in mice).
See Gilligan and Bennett (1993) for a review of adducin and the other components of the junctional complex of the cell membrane skeleton.
By somatic cell hybrid analysis, Joshi et al. (1991) provisionally assigned the ADD1 gene to chromosome 4 and the ADD2 gene to chromosome 2. Both alpha- and beta-adducin show alternative splicing; thus, there may be several different heterodimeric or homodimeric forms of adducin, each with a different functional specificity.
Using the technique of 'exon trapping' devised by Buckler et al. (1991), Taylor et al. (1992) identified exons corresponding to the alpha subunit of adducin within the 4p16.3 region where Huntington disease appeared to be located. They mapped the ADD1 gene immediately telomeric to D4S95.
Goldberg et al. (1992) reported the isolation and cloning of cDNA for the brain alpha-adducin gene, which they found to be located within 20 kb of D4S95.
Nasir et al. (1994) used an interspecific backcross to map the mouse Add1 gene to chromosome 5, within the region of syntenic homology with the short arm of human chromosome 4. Grosson et al. (1994) also mapped the mouse Add1 gene to chromosome 5 in a continuous linkage group that included the Huntington disease homolog.
Kuhlman et al. (1996) found that purified human erythrocyte adducin completely blocked elongation and depolymerization at the fast-growing barbed ends of actin filaments in vitro, thus functioning as a barbed end capping protein. This barbed end capping activity required the intact adducin molecule and was downregulated by calmodulin in the presence of calcium. Kuhlman et al. (1996) concluded that adducin restricts actin filament length in erythrocytes.
To investigate the molecular involvement of alpha-adducin in controlling Na/K pump activity, Torielli et al. (2008) transfected wildtype or mutated rat and human ADD1 into several renal cell lines and demonstrated that the rat and human mutated forms increased Na/K pump activity and the number of pump units; both variants coimmunoprecipitated with the Na/K pump. The increased pump activity was not due to changes in its basolateral location, but to an alteration of Na/K pump residential time on the plasma membrane. Both the rat and human mutated variants reduced constitutive Na/K pump endocytosis and similarly affected transferrin receptor (190010) trafficking and fluid-phase endocytosis. Alpha-adducin was also detected in clathrin (see 118955)-coated vesicles and coimmunoprecipitated with clathrin. Torielli et al. (2008) suggested that adducin, in addition to having modulatory effects on actin cytoskeleton dynamics, might play a direct role in clathrin-dependent endocytosis, and that the constitutive reduction of Na/K pump endocytic rate induced by mutated adducin variants might be relevant in sodium-dependent hypertension (see 145500).
In a case-control study involving 190 patients with primary hypertension and 126 controls, Casari et al. (1995) found an association between essential hypertension (see 145500) and allelic markers near the alpha-adducin locus.
Cusi et al. (1997) found significant linkage of the alpha-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with a particular ADD1 allele, trp460 (102680.0001), suggesting that alpha adducin is associated with a salt-sensitive form of essential hypertension.
Manunta et al. (1998) analyzed the pressure-natriuresis relationship in 108 hypertensive individuals and found that patients with a G/W or W/W ADD1 genotype showed lower plasma renin activity and fractional excretion of sodium as well as reduced slope of the pressure-natriuresis relationship after sodium depletion or sodium loading compared to G/G patients. These findings supported the hypothesis that individuals with at least 1 ADD1 460W allele have increased renal tubular sodium reabsorption.
Using endogenous lithium and uric acid as markers of proximal tubular sodium reabsorption, Manunta et al. (1999) investigated the relationship between renal sodium handling and ADD1 polymorphism in untreated hypertensive patients and found that adducin genotype was significantly and directly related to the fractional excretion of lithium. Manunta et al. (1999) concluded that ADD1 represents a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport sodium and thus affects blood pressure levels.
Allayee et al. (2001) performed a genomewide scan for blood pressure in 18 Dutch families exhibiting the common lipid disorder familial combined hyperlipidemia (144250). They found a locus on chromosome 4 that exhibited a significant lod score of 3.9 for systolic blood pressure. In addition, this locus appeared to influence plasma free fatty acid levels (lod = 2.4). After adjustment for age and gender, the lod score for systolic blood pressure increased to 4.6, whereas the lod score for free fatty acid levels did not change. Allayee et al. (2001) tested for an association between 2 intragenic ADD1 polymorphisms and systolic blood pressure in this sample and found none.
Lanzani et al. (2005) examined the association between polymorphisms in the ADD1, ADD2, and ADD3 genes (G460W, C1797T, and IVS11+386A-G, respectively) and ambulatory blood pressure and plasma levels of renin activity and endogenous ouabain in 512 newly discovered and never-treated hypertensive patients. Relative to carriers of the wildtype (G/G) ADD1 gene, carriers of the mutant 460W allele had higher blood pressure and lower plasma renin activity and endogenous ouabain levels. Polymorphisms in the ADD2 and ADD3 genes taken alone were not associated with these variables, but the blood pressure difference between the 2 ADD1 genotypes was greatest in carriers of the ADD3 G allele (increased by approximately 8 mm Hg; p = 0.020 to 0.006, depending on the genetic model applied). The authors suggested that there were epistatic effects between the ADD1 and ADD3 loci affecting variation in blood pressure.
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.
Tripodi et al. (1996) studied the effects of the Milan hypertensive rat 316Y and 529R mutations in Add1 and Add2, respectively, on actin polymerization and bundling in a cell-free system and found that double-mutated adducin exerted only a slight inhibitory effect with a much higher final extent of polymerization compared to wildtype. Adducin heterodimer mutated only in the beta subunit behaved as normal adducin, whereas adducin heterodimer mutated only in the alpha subunit exhibited an intermediate phenotype, consistent with the associated levels of blood pressure previously described by Bianchi et al. (1994). Studies of the actin cytoskeleton in transfected rat kidney epithelial cell lines showed that cells overexpressing the mutated alpha-adducin chain exhibited larger microfilament bundles and larger focal contacts with patchy aggregates of alpha-v integrin (193210), compared to cells overexpressing wildtype adducin, in which the microfilament bundles were organized in a much looser texture and alpha-v integrin was present in a diffuse punctate pattern with small focal contacts. The surface expression of the Na-K pump alpha subunit was considerably increased in cells overexpressing the mutated alpha-adducin chain, and Na-K pump activity at V(max) was increased with respect to normal transfected lines and untransfected cells. Tripodi et al. (1996) suggested that adducin has a role in the constitutive capacity of the renal epithelia both to transport ions and to expose adhesion molecules.
Efendiev et al. (2004) studied Milan rats carrying the hypertensive adducin phenotype and observed higher renal tubule Na/K-ATPase activity and found that their Na/K-ATPase molecules did not undergo endocytosis in response to dopamine like those of normotensive rats. In the hypertensive rats, dopamine failed to promote the interaction between adaptins (see 601026) and the Na/K-ATPase, required for endocytosis, because of adaptin-mu-2 subunit (602296) hyperphosphorylation. Expression of the hypertensive rat or human variant of ADD1 into normal renal epithelial cells recreated the hypertensive phenotype with higher Na/K-ATPase activity, mu-2-subunit hyperphosphorylation, and impaired Na/K-ATPase endocytosis. The authors concluded that increased renal Na/K-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na/K-ATPase endocytosis in response to natriuretic signals.
Cusi et al. (1997) found a significant association between a gly460-to-trp polymorphism (G460W) in the ADD1 gene and salt sensitivity in patients with essential hypertension (see 145500). Patients with the W460 allele showed greater sensitivity to changes in sodium balance, and heterozygous hypertensive patients (G/W) showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide, than did wildtype homozygous (G/G) hypertensive patients. In controls in an Italian cohort, the G460 allele had a frequency of 86.4% and the W460 allele 13.6%.
Manunta et al. (1998) analyzed the pressure-natriuresis relationship in 108 hypertensive individuals, 80 of whom were wildtype homozygous (G/G), 26 G/W heterozygous, and 2 W/W homozygous. At baseline, the G/W and W/W patients showed lower plasma renin activity and fractional excretion of sodium; these patients also had reduced slope of the pressure-natriuresis relationship after sodium depletion or sodium loading compared to G/G patients. These findings supported the hypothesis that individuals with at least 1 ADD1 460W allele have increased renal tubular sodium reabsorption.
Using endogenous lithium and uric acid as markers of proximal tubular sodium reabsorption, Manunta et al. (1999) investigated the relationship between renal sodium handling and ADD1 polymorphism in 54 untreated hypertensive patients, 29 with the G/G genotype and 25 with the G/W genotype. Fractional excretions of lithium and uric acid were significantly decreased in G/W patients compared to G/G patients; multiple regression analysis showed that adducin genotype was significantly and directly related to the fractional excretion of lithium. Manunta et al. (1999) concluded that ADD1 represents a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport sodium and thus affects blood pressure levels.
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