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PubMed1994

Identification as beta-adducin of a protein interacting with rabphilin-3A in the presence of Ca2+ and phosphatidylserine.

Rabphilin-3A is a putative target protein for Rab3A small GTP-binding protein implicated in neurotransmitter release. We have previously identified a Rabphilin-3A-interacting protein with a Mr of about 115 kDa in bovine brain. We have attempted here to purify this protein and to determine its primary structure. Amino acid sequence analysis has revealed that this protein is a bovine counterpart of human beta-adducin which is known to be a good substrate for protein kinase C. The Rabphilin-3A-interacting protein also binds to protein kinase C in the presence of Ca2+ and phosphatidylserine. These results indicate that Rabphilin-3A binds to beta-adducin in the presence of Ca2+ and phosphatidylserine.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Genomic organization of the human gamma adducin gene.

We report the genomic structure of the human gamma adducin gene (ADD3). Adducin is a protein involved in cytoskeletal assembly and composed of alpha-beta or alpha-gamma subunits which share a high degree of homology between human and rat. Mutations in alpha subunit have been shown associated to both human and rat hypertension. The human ADD3 gene spans over 20 kb and is composed of at least 13 introns and 14 exons covering the entire coding region. The exon size ranges from 81 bp to greater than 293 bp and the intron size from 111 bp to longer than 3.2 kb. We also demonstrate the presence of an alternative splicing event around exon 13, whose sequence, position, and expression is analogous in rat Add3 gene. Moreover, human ADD3 amino acid sequence presents 91.9% of identity compared to rat sequence. Characterization of human ADD3 gene provides an important tool for mutation analysis.

Alternative Splicing↗
PubMed1991

Immunofluorescence localization of an adducin-like protein in the chromosomes of mouse oocytes.

The mouse oocyte expresses a polypeptide of Mr 120,000 that cross-reacts with an antibody to the brain membrane skeletal protein adducin. Immunofluorescence localization showed a bright chromosomal staining reaction in metaphase I and metaphase II oocytes. Following in vitro fertilization the maternal chromosomes lost their immunoreactivity during pronuclear development. The fertilizing sperm chromatin and male pronucleus did not show any detectable staining reaction. Bright chromosomal fluorescence was again observed in the first mitotic metaphase when both maternal and paternal chromosomes gave a positive staining reaction. In contrast to the immunoreactivity of the maternal meiotic chromosomes, the meiotic chromosomes of male germ line cells failed to exhibit any detectable staining reaction and this difference was confirmed by immunolabeling of oocyte and spermatocyte karyotypes. Mitotic chromosomes in preimplantation embryos, fetal liver, adult intestinal epithelium, and MDCK cells also failed to show any detectable labeling reaction. The results suggest that expression of the immunoreactive chromosomal adducin may be a unique feature of oogenesis.

Animals↗
PubMed2000

Lack of evidence for an association between alpha-adducin and blood pressure regulation in Asian populations.

Recent studies have found the tryptophan allele of a glycine to tryptophan polymorphism at position 460 (G460W) of the alpha-adducin protein to be associated with essential hypertension in European populations. We examined whether the tryptophan allele is associated with hypertension in a different population, comprised of subjects of Chinese origin from Taiwan, and Chinese and Japanese origin from the San Francisco Bay area and Hawaii. We adapted the 5' allelic discrimination assay or TaqMan to type individuals for the G460W polymorphism, and using this method we typed more than 1000 individuals. The frequency of the W allele was slightly increased in the treated subjects in the Chinese population (0.458 v 0.423) but not the Japanese population (0.549 v 0.558). We considered dominant, recessive, and additive models in our analysis. There was a significant result for a recessive model for systolic blood pressure in the Chinese population (chi2 6.84, df = 2, P < .05), but only suggestive evidence for diastolic blood pressure (chi2 3.30). In contrast, in the Japanese population, there was no evidence for a positive association under any model. For the combined Chinese and Japanese samples, the evidence for association with alpha-adducin was not significant.

Adult↗
PubMed2000

Alpha-adducin polymorphism in hypertensives of South African ancestry.

The alpha-adducin gene contributes significantly to hypertension in MHS rats (rats of the Milan hypertensive strain) and in some white and Japanese populations, causing a low renin, sodium, and diuretic-sensitive hypertension. No data are available from populations of African ancestry who have a high prevalence of low renin, sodium, and diuretic-sensitive hypertension. We studied the relationship between the 460-Trp variant of alpha-adducin gene with hypertension using a case-control study design in black South Africans. Surprisingly we found that the overall frequency of the 460-Trp allele was low (approximately 6%), but in spite of such relatively low frequency, the 460-Trp allele was 2.5-fold more frequent in hypertensives than normotensives (P = .028), with an odds ratio for hypertension associated to the state of carrier of at least one 460-Trp allele of 2.68. The finding of such low frequency of the 460-Trp allele in individuals of African ancestry points to the substantial ethnic variability of the genes that have been found to be associated with hypertension. On the other hand, it suggests an association of the 460-Trp allele with hypertension also in subjects of African origin.

Adult↗
PubMed2003

Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide.

BACKGROUND: Pharmacogenetic discoveries may enable greater individualization of antihypertensive drug therapy. We investigated polymorphisms in the genes encoding endothelial nitric oxide synthase (Glu298-->Asp), alpha-adducin (Gly460-->Trp), the beta(1)-adrenoceptor (Arg389-->Gly), beta2-adrenoceptor (Arg16-->Gly), and lipoprotein lipase (Ser447-->Stop) for their potential influences on blood pressure (BP) response to a thiazide diuretic. METHODS: The sample consisted of 291 unrelated non-Hispanic African American adults (150 women and 141 men) and 294 unrelated non-Hispanic white adults (126 women and 168 men) who were between 30 and 59.9 years of age and who had essential hypertension. Previous antihypertensive drug therapy was withdrawn for at least 4 weeks, and subjects were then treated with hydrochlorothiazide (25 mg daily) for 4 weeks to determine BP response. RESULTS: The covariates of ethnicity, gender, age, and waist-to-hip ratio accounted for 26% of interindividual variation in systolic BP response and 11% of interindividual variation in diastolic BP response. After adjustment for covariates, the endothelial nitric oxide synthase Glu298-->Asp polymorphism made an additional statistically significant contribution to predicting diastolic BP response to hydrochlorothiazide, accounting for another 1% of interindividual variation in response (P =.034). In contrast, the other polymorphisms, including the alpha-adducin Gly460-->Trp polymorphism, made no statistically significant contributions to prediction of BP response. CONCLUSIONS: Although we reject the null hypothesis of no genetic effects on BP response to hydrochlorothiazide, the influence of variation at single sites is likely to be small. More extensive characterization of genetic variation is required for pharmacogenetic approaches to become clinically useful in tailoring antihypertensive drug therapy for individual patients.

Adult↗
PubMed1999

The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians.

A Gly460Trp variant of the cytoskeletal protein alpha-adducin has recently been implicated in the etiology of essential hypertension (HT) in a study involving southern European whites. We attempted to replicate this finding in a well-characterized, extensively studied group of 112 white Australians with essential HT, with strong family history (two HT parents), early-onset, moderate to severe disease, and of British extraction. Controls were 196 normotensive (NT) white subjects whose parents were both NT older than age 50 years. A mismatch polymerase chain reaction method involving BanII was developed for genotyping. Frequency of the Trp460 allele was 0.23 in the HT and 0.24 in the NT groups (chi2 = 0.2, P = .7). No association was observed with blood pressure, body mass index, age, plasma renin, angiotensinogen, angiotensin converting enzyme, cholesterol, triglycerides, or HDL or LDL cholesterol. Our results therefore provide no support for a role for the alpha-adducin variant in hypertension, at least in our severely affected Anglo-white group with strong family history of HT.

Alleles↗
PubMedDate not supplied

Modulation of spectrin-actin assembly by erythrocyte adducin.

The spectrin-based membrane skeleton, an assembly of proteins tightly associated with the plasma membrane, determines the shape and mechanical properties of erythrocytes. Spectrin, the most abundant component of this assembly, is an elongated and flexible molecule that, with potentiation by protein 4.1, is cross-linked at its ends by short actin filaments to form a lattice beneath the membrane. These and other proteins stabilize the plasma membrane, organize integral membrane proteins and maintain specialized regions of the cell surface. A membrane-skeleton-associated calmodulin-binding protein of erythrocytes is a major substrate for Ca2+- and phospholipid-dependent protein kinase C (ref. 5), and thus is a target for Ca2+ by two regulatory pathways. Here we demonstrate that this protein, called adducin: (1) binds tightly in vitro to spectrin-actin complexes but with much less affinity either to spectrin or to actin alone; (2) promotes assembly of additional spectrin molecules onto actin filaments; and (3) is inhibited in its ability to induce the binding of additional spectrin molecules to actin by micromolar concentrations of calmodulin and Ca2+. Adducin may be involved in the action of Ca2+ on erythrocyte membrane skeleton and in the assembly of spectrin-actin complexes.

Actins↗
PubMed2006

The influence of the alpha-adducin G460W polymorphism and angiotensinogen M235T polymorphism on antihypertensive medication and blood pressure.

Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients. The aim of this study was investigate whether the alpha-adducin G460W polymorphism or angiotensinogen M235T polymorphism has an effect on the mean difference in blood pressure in subjects using antihypertensive drugs. Data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, was used. This study started in 1990 and included 7983 subjects of 55 years and older. Data from three examination rounds were used. Subjects were included when their blood pressure was elevated at 1 or more examinations and/or a diuretic, beta-blocker, calcium antagonist, or ACE inhibitor was used. A marginal generalized linear model was used to assess the drug-gene interaction. In total, 3025 hypertensives were included. No drug-gene interaction on blood pressure levels was found. The mean difference in systolic blood pressure (SBP) between subjects with the W-allele and GG genotype of the alpha-adducin gene was for diuretic users 1.25 mmHg (95% CI:-2.86 to 5.35), for beta-blockers 0.02 mmHg (95% CI:-3.39 to 3.42), for calcium antagonists -0.70 mmHg (95% CI:-5.61 to 4.21), and for ACE inhibitors -3.50 mmHg (95% CI:-9.02 to 2.02). The mean difference in SBP between subjects with the TT and MM genotype was for diuretic users -2.33 mmHg (95% CI:-8.32 to 3.66), for beta-blocker -0.06 mmHg (95% CI:-4.91 to 4.79), for calcium antagonist 0.59 mmHg (95% CI:-5.95 to 7.13), and for ACE inhibitor -2.33 mmHg (95% CI:-9.66 to 5.01). The G460W polymorphism and the M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors.

Adrenergic beta-Antagonists↗
PubMed2006

Antihypertensive therapy, the alpha-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study.

In a double-blind, outcome trial conducted in hypertensive patients randomized to chlorthalidone (C), amlodipine (A), lisinopril (L), or doxazosin (D), the alpha-adducin Gly460Trp polymorphism was typed (n=36 913). Mean follow-up was 4.9 years. Relative risks (RRs) of chlorthalidone versus other treatments were compared between genotypes (Gly/Gly+Gly/Trp versus Trp/Trp). Primary outcome was coronary heart disease (CHD). Coronary heart disease incidence did not differ among treatments or genotypes nor was there any interaction between treatment and genotype (P=0.660). Subgroup analyses indicated that Trp allele carriers had greater CHD risk with C versus A+L in women (RR=1.31) but not men (RR=0.91) with no RR gender differences for non-carriers (gender-gene-treatment interaction, P=0.002). The alpha-adducin gene is not an important modifier of antihypertensive treatment on cardiovascular risk, but women Trp allele carriers may have increased CHD risk if treated with C versus A or L. This must be confirmed to have implications for hypertension treatment.

Aged↗
PubMed1993

Different genetic requirements for anterior RNA localization revealed by the distribution of Adducin-like transcripts during Drosophila oogenesis.

The proteins encoded by polar-localized mRNAs play an important role in cell fate specification along the anteroposterior axis of the Drosophila embryo. The only maternally synthesized mRNA known previously to be localized to the anterior cortex of both the oocyte and the early embryo is the bicoid mRNA whose localization is required to generate a homeodomain protein gradient that specifies position along the anteroposterior embryonic axis. We have identified and characterized a second mRNA that is localized to the anterior pole of the oocyte and early embryo. This mRNA encodes a Drosophila homolog of mammalian adducin, a membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. A comparison of the spatial distribution of bicoid and Adducin-like transcripts in the maternal-effect RNA-localization mutants exuperantia, swallow, and staufen indicates different genetic requirements for proper localization of these two mRNAs to the anterior pole of the oocyte and early embryo.

Amino Acid Sequence↗
PubMed1992

hu-li tai shao, a gene required for ring canal formation during Drosophila oogenesis, encodes a homolog of adducin.

Drosophila females bearing mutations in a previously undescribed gene, hu-li tai shao [(hts) too little nursing], produced egg chambers that contained fewer than the normal 15 nurse cells and that usually lacked an oocyte. The cytoplasmic bridges (ring canals) interconnecting nurse cells and the oocyte appeared abnormal, and lacked associated actin rings. The hts locus was found to encode a homolog of the mammalian membrane skeletal protein adducin. During oogenesis, hts mRNA became localized at the anterior of the oocyte and was subsequently expressed in a variety of embryonic tissues. These studies suggested that Drosophila adducin is needed to assemble actin at specialized regions of cell-cell contact in developing egg chambers and may also function at other times during the Drosophila life cycle.

Amino Acid Sequence↗
PubMed2001

Lack of association between Gly460Trp polymorphism of alpha-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.

BACKGROUND: Previous studies have suggested that alpha-adducin (alpha-ADD) polymorphism may identify patients with a salt-sensitive form of hypertension. AIM: To investigate the association between Gly460Trp polymorphism of alpha-ADD and the pattern of blood pressure response to subacute (1 week) salt loading and depletion in young adult thin Polish hypertensives. METHODS: The study group consisted of 44 subjects with salt-sensitive hypertension (SS) and 24 subjects with non-salt-sensitive hypertension (SR). Genomic DNA isolated from peripheral blood leukocytes was amplified by PCR method with primers flanking the polymorphic region. The mismatch near to 3'-end of the upstream primer was introduced to create a Nla III restriction site in Trp 460 allele. In addition, excreted fraction of filtered sodium (FENa), plasma renin activity (PRA) and plasma concentrations of aldosterone (ALDO) were determined on normal, low and high salt diets. RESULTS: FENa on normal or high salt diets were significantly lower in the SS hypertensives as compared with the SR patients. PRA in SS group was also significantly lower as compared with results in SR group, but only on high salt diet. No significant difference was detected in frequencies of genotypes and alleles of alpha-ADD gene between SS and SR subjects. An additional analysis with regard to genotype (Gly/Gly vs. Gly/Trp+Trp/Trp) showed no significant difference in changes of blood pressure as well as in results of laboratory investigations. CONCLUSION: Our results suggest lack of association between Gly460Trp polymorphism of alpha-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.

Adult↗
PubMed2004

Alpha-adducin Gly460Trp polymorphism and renal hemodynamics in essential hypertension.

Previous studies have shown an association between the alpha-adducin Gly460Trp polymorphism and salt-sensitive hypertension. Not much is known about the effects of the variants of this polymorphism on renal hemodynamics and function. Therefore, we performed the present study to investigate the effect of the 460Trp allele of the alpha-adducin gene on renal hemodynamics in one hundred and seventeen essential hypertensive patients who were put on a low and high sodium diet (randomized order). On the last day of each one-week dietary period, blood pressure, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), and neurohormones were measured. Effective renal blood flow (ERBF), renal vascular resistance, and filtration fraction were calculated. ERPF, ERBF, and GFR were lower in patients homozygous for the 460Trp allele compared with patients with the Gly460Gly genotype on low sodium diet but no differences were found at the higher sodium intake. On the other hand, levels of atrial natriuretic peptide were significantly higher in patients with the Trp460Trp genotype as compared with patients with the Gly460Gly genotype on both diets. In multivariate analysis, Trp460Trp genotype, age, and mean arterial pressure were predictors of ERPF, whereas Trp460Trp genotype and age were predictors of GFR during the phase of low sodium diet. The present study shows that the Trp460Trp genotype is significantly associated with reduced renal plasma flow and glomerular filtration rate as compared with the wild-type variant.

Adult↗
PubMed2006

Analysis of a homologue of the adducin head gene which is a potential target for the Dictyostelium STAT protein Dd-STATa.

A Dd-STATa-null mutant, which is defective in expression of a Dictyostelium homologue of the metazoan STAT (signal transducers and activators of transcription) proteins, fails to culminate and this phenotype correlates with the loss of expression of various prestalk (pst) genes. An EST clone, SSK395, encodes a close homologue of the adducin amino-terminal head domain and harbors a putative actin-binding domain. We fused promoter fragments of the cognate gene, ahhA (adducin head homologue A), to a lacZ reporter and determined their expression pattern. The proximal promoter region is necessary for the expression of ahhA at an early (pre-aggregative) stage of development and this expression is Dd-STATa independent. The distal promoter region is necessary for expression at later stages of development in pstA cells, of the slug and in upper cup and pstAB cells during culmination. The distal region is partly Dd-STATa-dependent. The ahhA-null mutant develops almost normally until culmination, but it forms slanting culminants that tend to collapse on to the substratum. The mutant also occasionally forms fruiting bodies with swollen papillae and with constrictions in the prestalk region. The AhhA protein localizes to the stalk tube entrance and also to the upper cup cells and in cells at or near to the constricted region where an F-actin ring is localized. These findings suggest that Dd-STATa regulates culmination and may be necessary for straight downward elongation of the stalk, via the putative actin-binding protein AhhA.

Actins↗
PubMed2004

Ubiquitination of erythrocyte spectrin regulates the dissociation of the spectrin-adducin-f-actin ternary complex in vitro.

We demonstrate that ubiquitinated red blood cell (RBC) spectrin dissociates more rapidly from the spectrin-adducin-actin ternary complex, than non-ubiquitinated spectrin. Homozygous (SS) sickle cell spectrin has substantially diminished ubiquitination of alpha-spectrin resulting in slower dissociation from the spectrin-adducin-actin ternary complex, than normal (AA) cell spectrin. These results supply a partial explanation of the slow dissociation of the irreversible sickle cell (ISC) membrane skeleton, which leads to the inability of the ISC to change shape.

Actins↗
PubMed2004

[Alpha-adducin gene G/W460 polymorphism is associated with intracerebral hemorrhage in Chinese].

OBJECTIVE: To explore the association between alpha-adducin (ADD1) G/W460 and intracerebral hemorrhage (ICH) in Chinese. METHODS: Samples of peripheral blood were collected from 456 patients with ICH diagnosed by CT or MRI from 7 clinical centers in China and 454 age, sex, and geographically matched subjects as controls. The ADD1 G/W460 polymorphism was detected by PCR. Information about prior exposure to various potential risk factors was collected by questionnaire survey. RESULTS: The distribution of ADD1gene G460W polymorphisms in the ICH patients and controls were in agreement with the Hardy-Weinberg proportion. The prevalence of 460W allele among ICH cases was 82.2%, higher than that in the controls (76.0%, crude odds ratio, 1.46; 95% CI, 1.05 to 2.05). The ADD1 460W allele was still significantly associated with ICH after adjustment for hypertension and other ICH putative risk factors (adjusted odds ratio, 1.38; 95% CI, 1.01 to 1.88). CONCLUSION: Alpha-adducin gene G/W 460 polymorphism is significantly associated with the risk of ICH. This association does not appear to be mediated by established ICH risk factors, specifically hypertension status.

Adult↗
PubMed2003

NUP98 is fused to adducin 3 in a patient with T-cell acute lymphoblastic leukemia and myeloid markers, with a new translocation t(10;11)(q25;p15).

The nucleoporin 98 gene (NUP98) has been reported to be fused to 13 partner genes in hematological malignancies with 11p15 translocations. Twelve of them have been identified in patients with myeloid neoplasias and only 1, RAP1GDS1 (4q21), is fused with NUP98 in five patients with T-cell acute lymphoblastic leukemia (T-ALL). Three of these patients coexpressed T and myeloid markers, suggesting the specific association of t(4;11)(q21;p15) with a subset of T-ALL originating from an early progenitor, which has the potential to express mature T-cell antigens as well as myeloid markers. We describe here a new NUP98 partner involved in a t(10;11)(q25;p15) in a patient with acute biphenotypic leukemia, showing coexpression of mature T and myeloid markers. The gene involved, located in 10q25, was identified as ADD3 using 3'-RACE. ADD3 codes for the ubiquitous expressed subunit gamma of the adducin protein, and it seems to play an important role in the skeletal organization of the cell membrane. Both NUP98-ADD3 and ADD3-NUP98 fusion transcripts are expressed in the patient. This is the second partner of NUP98 described in T-ALL. Adducin shares with the product of RAP1GDS1, and with all of the nonhomeobox NUP98 partners, the presence of a region with significant probability of adopting a coiled-coil conformation. This region is always retained in the fusion transcript with the NH(2) terminus FG repeats of NUP98, suggesting an important role in the mechanism of leukemogenesis.

Adult↗