Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: SLC4A1
SNOMEDCT: 236461000, 723623002, 85129003;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:44,248,390-44,268,135 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | [Blood group, Diego] | 110500 | 3 | |
| [Blood group, Froese] | 601551 | 3 | ||
| [Blood group, Swann] | 601550 | 3 | ||
| [Blood group, Waldner] | 112010 | 3 | ||
| [Blood group, Wright] | 112050 | 3 | ||
| {Malaria, resistance to} | 611162 | 3 | ||
| Cryohydrocytosis | 185020 | Autosomal dominant | 3 | |
| Distal renal tubular acidosis 1 | 179800 | Autosomal dominant | 3 | |
| Distal renal tubular acidosis 4 with hemolytic anemia | 611590 | Autosomal recessive | 3 | |
| Ovalocytosis, SA type | 166900 | Autosomal dominant | 3 | |
| Spherocytosis, type 4 | 612653 | Autosomal dominant | 3 |
Band 3 is the major glycoprotein of the erythrocyte membrane. It mediates exchange of chloride and bicarbonate across the phospholipid bilayer and plays a central role in respiration of carbon dioxide. It is a 93,000-Da protein composed of 2 distinct domains that function independently. The 50,000-Da C-terminal polypeptide codes for the transmembrane domain that is involved in anion transport. The 43,000-Da cytoplasmic domain anchors the membrane cytoskeleton to the membrane through an ankyrin-binding site (band 2.1) and also contains binding sites for hemoglobin and several glycolytic enzymes. Proteins related to red cell band 3 have been identified in several types of nucleated somatic cells (review by Palumbo et al., 1986).
Lux et al. (1989) cloned human band 3 from a fetal liver cDNA library. The deduced 911-amino acid protein is similar in structure to other anion exchangers and is divided into 3 regions: a hydrophobic, cytoplasmic domain that interacts with a variety of membrane and cytoplasmic proteins (residues 1-403); a hydrophobic, transmembrane domain that forms the anion antiporter (residues 404-882); and an acidic, C-terminal domain (residues 883-911). Lux et al. (1989) presented a model in which the protein crosses the membrane 14 times.
Langdon and Holman (1988) concluded that band 3 constitutes the major glucose transporter of human erythrocytes. A monoclonal antibody to band 3 specifically removed band 3 and more than 90% of the reconstitutable glucose transport activity from extracts of erythrocyte membranes; nonimmune serum removed neither. Band 3 is probably a multifunctional transport protein responsible for transport of glucose, anions, and water.
Senescent cell antigen (SCA), an aging antigen, is a protein that appears on old cells and marks them for removal by the immune system. The aging antigen is generated by the degradation of protein band 3. Besides its role in the removal of senescent and damaged cells, SCA also appears to be involved in the removal of erythrocytes in hemolytic anemias and the removal of malaria-infected erythrocytes. Band 3 is found in diverse cell types and tissues besides erythrocytes, including hepatocytes, squamous epithelial cells, lung alveolar cells, lymphocytes, kidney, neurons, and fibroblasts. It is also present in nuclear, Golgi, and mitochondrial membranes. Kay et al. (1990) used synthetic peptides to identify antigenic sites on band 3 recognized by the IgG that binds to old cells.
Tanner (1993) discussed the molecular and cellular biology of the erythrocyte anion exchanger, band 3. It permits the high rate of exchange of chloride ion by bicarbonate ion across the red cell membrane: the efflux of bicarbonate from the cell in exchange for plasma chloride ion in the capillaries of the tissues (the Hamburger shift, or chloride ion shift) and the reverse process in lung capillaries. At least 2 nonerythroid anion exchange genes have been characterized, AE2 (109280) and AE3 (106195), and tentative evidence for a fourth member of the class, AE4 (SLC4A9; 610207), was mentioned. The ability of AE2 and AE3 to mediate anion transport has been confirmed. As outlined by Tanner (1993), it is not strictly accurate to refer to the AE1 gene as being that for the erythroid anion exchanger because the AE1 gene is expressed in some nonerythroid tissues, where it appears to be transcribed from different tissue-specific promoters.
Watts et al. (1996) determined that both ZAP70 (176947) and LCK (153390) can phosphorylate the cytoplasmic fragment of BND3. However, these 2 protein tyrosine kinases act on different sites of the BND3 protein.
Pawloski et al. (2001) demonstrated that in human erythrocytes hemoglobin-derived S-nitrosothiol (SNO), generated from imported nitric acid (NO), is associated predominantly with the red blood cell membrane, and principally with cysteine residues in the hemoglobin-binding cytoplasmic domain of the anion exchanger AE1. Interaction with AE1 promotes the deoxygenated structure in SNO-hemoglobin, which subserves NO group transfer to the membrane. Furthermore, Pawloski et al. (2001) showed that vasodilatory activity is released from this membrane precinct by deoxygenation. Thus, the oxygen-regulated cellular mechanism that couples the synthesis and export of hemoglobin-derived NO bioactivity operates, at least in part, through formation of AE1-SNO at the membrane-cytosol interface.
Goel et al. (2003) identified a sialic acid-independent host-parasite interaction involved in the Plasmodium falciparum malaria parasite invasion of red blood cells. They showed that 2 nonglycosylated extracellular regions of band 3 function as a crucial host receptor. They identified 2 processing products of merozoite surface protein-1 (MSP1) as major parasite ligands binding to the band 3 receptor.
Bruce et al. (2004) studied the properties of band 3 in red cells lacking glycophorin A (GPA; 617922) and found that sulfate, iodide, and chloride transport were reduced. Increased flexibility of the membrane domain of band 3 was associated with reduced anion transport activity. Bruce et al. (2004) suggested that band 3 in the red cell can take up 2 different structures: one with high anion transport activity when GPA is present and one with lower anion transport activity when GPA is absent.
By yeast 2-hybrid analysis, affinity copurification, coimmunoprecipitation, and fluorescence-based protein fragment complementation, Nuiplot et al. (2015) confirmed direct interaction between TMEM139 and the kidney isoform of AE1 (kAE1). Knockdown of TMEM139 expression in HEK293T cells reduced membrane localization of kAE1. In contrast, overexpression of TMEM139 increased kAE1 surface expression.
Schofield et al. (1994) demonstrated that the EPB3 gene extends over 18 kb and consists of 20 exons. The cDNA sequence comprises 4,906 nucleotides, excluding the poly(A) tail. They found extensive similarity between the human and mouse genes, although the latter covers 17 kb. The additional length of the human gene is mainly caused by the presence of 6 Alu repetitive units in the human gene between intron 13 and exon 20. Two potential promoter regions are positioned so that they could give rise to the different transcripts found in erythroid cells and in the kidney. The kidney transcript would lack exons 1 through 3 of the erythroid transcript. The translation initiator downstream to the human kidney promoter would give rise to a protein with a 20-amino acid section at the N-terminus that is not present in the erythroid protein. Sahr et al. (1994) concluded that the AE1 gene spans approximately 20 kb and consists of 20 exons separated by 19 introns. Its structure showed close similarity to that of the mouse AE1 gene. Sahr et al. (1994) described the upstream and internal promoter sequences of the human AE1 gene used in erythroid and kidney cells, respectively.
Crystal Structure
Arakawa et al. (2015) reported the crystal structure of the band 3 anion exchanger domain (AE1(CTD)) at 3.5 angstroms. The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed Arakawa et al. (2015) to identify the anion-binding position in the AE1(CTD), and to propose a possible transport mechanism that could explain why selected mutations lead to disease.
Showe et al. (1987) localized the gene for BND3 to 17q21-qter by Southern blot analysis of DNA from somatic cell hybrids.
Lux et al. (1989) confirmed assignment of the BND3 gene to chromosome 17.
According to HGM10, EPB3 is in the same large restriction fragment as RNU2 (180690), which narrows the localization to 17q21-q22. Using RFLPs of both loci, Stewart et al. (1989) showed that EPB3 is closely linked to NGFR (162010) (maximum lod = 11.40 at theta = 0.00, with a confidence limit of 0.00 to 0.04).
Gross (2018) mapped the SLC4A1 gene to chromosome 17q21.31 based on an alignment of the SLC4A1 sequence (GenBank BC096106) with the genomic sequence (GRCh38).
Mueller and Morrison (1977) and Hsu and Morrison (1985) reported variant forms of band 3 with an elongated N terminus. Both variants are hematologically normal with normal red cell morphologic features; the red cells do not appear to be resistant to invasion by malaria parasites in vitro (Ranney et al., 1990; Schulman et al., 1990).
Palatnik et al. (1990) described 3 phenotypes based on the polymorphism of band-3 protein from human red cells. Limited proteolysis of intact red cells from most individuals (homozygotes) yields a peptide of 60 kD, but in some persons (heterozygotes), there is also a 63-kD peptide, and rarely only the single peptide of 63 kD is found. This was the first description of the 63-kD homozygote. The frequency of the p63 allele was estimated to be 0.041 +/- 0.0068 in Caucasoids and 0.125 +/- 0.0121 in Negroids.
Acanthocytosis
Kay et al. (1987, 1988) reported 2 sibs with acanthocytosis whose red cells showed markedly increased anion transport activity. The sibs were clinically normal, the abnormality having been detected through the acanthocytosis found on blood studies for unrelated reasons. Kay et al. (1987, 1988) concluded that the 'disorder' was recessive. Bruce et al. (1993) studied the red cells of one of the sibs reported by Kay et al. (1988) and identified band 3 HT (109270.0032).
Southeast Asian Ovalocytosis
Following up on the demonstration by Liu et al. (1990) that a structurally and functionally abnormal band 3 protein shows absolute linkage with the Southeast Asian Ovalocytosis (SAO; 166900) phenotype, Jarolim et al. (1991) demonstrated that the EPB3 gene in these cases contains a 27-bp deletion, resulting in deletion of 9 amino acids (codons 400-408) in the boundary of cytoplasmic and membrane domains of the band 3 protein (109270.0002). The defect was detected in all 30 ovalocytic subjects from Malaysia, the Philippines, and 2 unrelated coastal regions of Papua New Guinea, whereas it was absent in all 30 controls from Southeast Asia and 20 subjects of different ethnic origin from the United States. The lys56-to-glu mutation (109270.0001) was also found in all SAO subjects; however, it was detected in 5 of 50 control subjects as well, suggesting that it represents a linked polymorphism.
Kidson et al. (1981) found that ovalocytic erythrocytes from Melanesians are resistant to invasion by malaria parasites, thus providing a plausible explanation for the polymorphism (also see Serjeantson et al., 1977). Baer (1988) suggested that Malaysian elliptocytosis may be a balanced polymorphism, i.e., that individuals homozygous for the elliptocytosis allele, not clearly identifiable by any assay, may be differentially susceptible to mortality, whereas the heterozygote is at an advantage. Hadley et al. (1983) showed that Melanesian elliptocytes are highly resistant to invasion by Plasmodium knowlesi and P. falciparum in vitro. This is the only human red cell variant known to be resistant to both.
Coetzer et al. (1996) described a 4-generation South African kindred with dominantly inherited ovalocytosis and hemolytic anemia. All affected subjects exhibited varying degrees of hemolytic anemia. Additionally, there was evidence for independent segregation of the band 3 Memphis I polymorphism (109270.0001) and the 27-bp deletion in BND3 causing SAO. Six SAO subjects and all 3 normal family members were heterozygous for the band 3 Memphis I polymorphism and one SAO subject was homozygous for this mutation.
Spherocytosis Type 4
In a 28-year-old female with congenital spherocytic hemolytic anemia (SPH4; 612653), Jarolim et al. (1991) identified a missense mutation in the SLC4A1 gene (109270.0003).
In a 33-year-old woman with pregnancy-associated hemolytic anemia and spherocytosis, Rybicki et al. (1993) identified a G40K mutation in SLC4A1 (109270.0004).
In a 3-generation Czech family in which 5 affected members exhibited compensated hemolytic disease, Jarolim et al. (1994) identified a 10-bp duplication in the SLC4A1 gene (109270.0005) that segregated with disease.
In affected members of a large Swiss family with spherocytosis, Maillet et al. (1995) identified heterozygosity for an SLC4A1 G771D mutation (109270.0007).
In an 18-year-old French man with moderate hereditary spherocytosis, Alloisio et al. (1996) identified an R150X mutation in SLC4A1 (109270.0009). The proband's mother, who had the same mutation, had a milder clinical presentation. Further investigation revealed a second, paternally inherited SLC4A1 mutation in the proband (109270.0010).
Dhermy et al. (1997) studied 8 kindreds with dominant hereditary spherocytosis and band 3 deficiency mutations. The amount of band 3 appeared to be slightly, but significantly, more reduced in HS patients with missense mutations and presence of the mutant transcripts than in HS patients with premature termination of translation and absence of mutant transcripts, suggesting that SLC4A1 missense mutations may have a dominant-negative effect.
Alloisio et al. (1997) reported a V488M mutation in band 3 (109270.0022) that was associated with spherocytosis in heterozygous state. Ribeiro et al. (2000) identified the V488M mutation in homozygosity in a female infant with severe anemia and hydrops, in whom renal tubular acidosis was detected by age 3 months.
In a 29-year-old Japanese man with compensated hemolytic anemia and spherocytosis, Inoue et al. (1998) identified homozygosity for an SLC4A1 G130R mutation (109270.0018).
In a 22-year-old Japanese man who presented with cholelithiasis and hemolysis and had a history of jaundice since early childhood, Iwase et al. (1998) identified a T837A mutation in SLC4A1 (band 3 Tokyo; 109270.0019).
Bruce et al. (2005) identified 11 human pedigrees with dominantly inherited hemolytic anemias, 8 in the hereditary stomatocytosis class (see 'Cryohydrocytosis,' below) and 3 in the spherocytosis class. Affected individuals in these families had an increase in membrane permeability to sodium and potassium ion that was particularly marked at zero degree centigrade. They found that disease in these pedigrees was associated with a series of single amino acid substitutions in the intramembrane domain of the band 3 anion exchanger. Anion movements were reduced in the abnormal red cells. The 'leak' cation fluxes were inhibited by chemically diverse inhibitors of band 3. Expression of the mutated genes in Xenopus laevis oocytes induced abnormal NA and K fluxes in the oocytes, and the induced chloride transport was low. These data were considered consistent with the suggestion that the substitutions convert the protein from an anion exchanger into an unregulated cation channel. All affected individuals were heterozygous for missense mutations in exon 17 of the SLC4A1 gene, including 2 families with spherocytosis who carried the R760Q mutation (109270.0028) that had previously been reported in 2 spherocytosis patients by Jarolim et al. (1995).
Cryohydrocytosis
In 8 unrelated families with cryohydrocytosis (CHC; 185020), Bruce et al. (2005) identified 3 different heterozygous missense mutations in the SLC4A1 gene (109270.0033-109270.0035) that segregated fully with disease in each family.
Choreoacanthocytosis
Tanner (1993) reviewed the evidence that mutations in the AE1 gene can cause choreoacanthocytosis (200150; see Kay, 1991). Kay et al. (1989) reported a band 3 alteration in association with anemia as determined by a reticulocyte count of 20%. The erythrocyte defect was reflected in increased IgG binding, increased breakdown products of band 3, and altered anion- and glucose-transport activity in middle-aged cells. IgG eluted from the red cells of the propositus appeared to have a specificity for senescent cell antigen. This and other studies suggested that band 3 was aging prematurely in erythrocytes of the subject, and that the senescent cell antigen appeared on the middle-aged red cells. Two sibs were affected. Both parents were thought to show 'subtle band 3 changes.' Autosomal recessive inheritance was postulated.
Distal Renal Tubular Acidosis 1, Autosomal Dominant
Bruce et al. (1997) found that all affected members of 4 families with autosomal dominant familial renal tubular acidosis (DRTA1; 179800) were heterozygous for mutations in the SLC4A1 gene; these mutations were not found in any of the 9 normal family members studied. In 2 families the mutation was arg589 to his (109270.0012); arg589-to-cys (109270.0013) and ser613-to-phe (109270.0014) changes were found in the other families. Linkage studies confirmed the cosegregation of the disease with a genetic marker close to SLC4A1. Affected individuals with the mutations in arg589 had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the ser613-to-phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 protein were expressed in Xenopus oocytes and all showed significant chloride transport activity. Bruce et al. (1997) concluded that dominantly inherited RTA is associated with mutations in band 3; however, both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins. Arg589 is located in the cytoplasmic loop between transmembrane segments 6 and 7 of band 3. This arginine is conserved in all known vertebrate sequences of AE1, AE2, and AE3, suggesting that it is functionally important. Arg589 is located in a cluster of basic residues which may form part of the cytoplasmic anion binding site of band 3. The mechanism by which the S613F mutation increases the affinity of the protein for sulfate was not clear. One possibility was that the mutation, which is located near the center of membrane span 7 and results in a substitution of serine by a bulky phenylalanine residue, altered the orientation of membrane span 7 relative to span 6. This may distort the conformation of the cytoplasmic loop between spans 6 and 7 which contains the putative anion binding site so that the clustered basic residues bind sulfate more tightly than the wildtype protein. Bruce et al. (1997) were prompted to undertake this study because of a possible association between dominant RTA and hereditary ovalocytosis (Baehner et al., 1968). Mutations in the families with dominant RTA were different from those affecting band 3 in Southeast Asian ovalocytosis. Complete absence of band 3 was found by Inaba et al. (1996) to result in defective renal acid secretion in cattle.
Most of the patients in the 4 families studied by Bruce et al. (1997) presented clinically with renal stones, and the majority had nephrocalcinosis. One patient in a family with the arg589-to-his mutation had rickets when initially seen at age 10 years and developed osteomalacia at the age of 31 after she stopped taking alkali therapy, but no other patient had bone disease. Eight patients were not acidotic when first seen, and were diagnosed as 'incomplete' dominant RTA because they were unable to excrete a urine more acid than pH 5.3 after oral acute ammonium chloride challenge. Compared with acidotic cases, these patients tended to be younger, with lower plasma creatinines, better preservation of urinary concentrating ability, and less (or no) nephrocalcinosis; over a 10-year period, 2 of the patients spontaneously developed acidosis. Acidotic patients were treated with oral alkalis, usually 6 gm of sodium bicarbonate daily, and had normal acid-base status at the time of the study; nonacidotic patients were not treated.
Karet et al. (1998) screened 26 kindreds with primary distal renal tubular acidosis for mutations in the AE1 gene. Inheritance was autosomal recessive in 17, autosomal dominant in 1, and uncertain due to unknown parental phenotype or sporadic disease in 8. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive distal RTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the 1 known dominant distal RTA kindred, in 1 sporadic case, and in 1 kindred with 2 affected brothers. In the dominant kindred, an arg589-to-ser mutation (109270.0015) cosegregated with distal RTA in the extended pedigree. In the sporadic case, an arg589-to-his mutation (109270.0012) proved to be a de novo change. In the third kindred, both affected brothers had an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1 (band 3 Walton; 109270.0025). Parental consanguinity was identified in 14 of the 17 recessive pedigrees. In the recessive kindreds, 19 of 25 patients were diagnosed at 1 year of age or less, and the remainder presented at 6 years or younger. All index cases presented either acutely with vomiting and dehydration, or with failure to thrive or delayed growth. Younger affected sibs were often diagnosed prospectively. All patients with the recessive disease were found to have nephrocalcinosis, nephrolithiasis, or both, and several had rickets. Nine of these patients from 6 families also had bilateral sensorineural deafness confirmed by audiometry; see renal tubular acidosis with progressive nerve deafness (267300). In contrast, in the 1 dominant kindred (with the arg589-to-ser mutation), 2 propositae were diagnosed because of nephrolithiasis at ages 56 and 36 years. Prospective screening identified other affected family members who were all asymptomatic, and most were diagnosed in adulthood. None of the 6 affected members of this family had radiologic evidence of nephrocalcinosis.
The chloride-bicarbonate exchanger AE1, which is mutant in autosomal dominant distal renal tubular acidosis, is normally expressed at the basolateral surface of alpha-intercalated cells in the distal nephron. Devonald et al. (2003) demonstrated that AE1 is aberrantly targeted to the apical surface in this disorder, in contrast with many disorders where mutant membrane proteins are retained intracellularly and degraded.
Distal Renal Tubular Acidosis 4 with Hemolytic Anemia
Tanphaichitr et al. (1998) described novel AE1 mutations in a Thai family with a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport was normal (DRTA4; 611590). A brother and sister were triply homozygous for 2 benign mutations, M31T and K56E (109270.0001), and for a loss-of-function mutation, G701D (109270.0016). The AE1 G701D loss-of-function mutation was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression of the erythroid AE1 chaperonin, glycophorin A, along with the AE1 G701D mutation, rescued both AE1-mediated chloride ion transport and AE1 surface expression in oocytes. The genetic and functional data suggested that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.
Bruce et al. (2000) studied 3 Malaysian and 6 Papua New Guinean families with dRTA and Southeast Asian ovalocytosis (SAO). The SAO deletion mutation (109270.0002) occurred in many of the families but did not itself result in distal renal tubular acidosis. Compound heterozygotes of each of the 3 dRTA mutations (G701D, 109270.0016; A858D, 109270.0020; delV850 109270.0021) with SAO all had dRTA, evidence of hemolytic anemia, and abnormal red cell properties. The A858D mutation showed dominant inheritance and the recessive delV850 and G701D mutations showed a pseudodominant phenotype when the transport-inactive SAO allele was also present. Red cell and Xenopus oocyte expression studies showed that the delV850 and A858D mutant proteins had greatly decreased anion transport when present as compound heterozygotes with each other or with SAO. Red cells with A858D/SAO had only 3% of the sulfite ion efflux of normal cells, the lowest anion transport activity reported for human red cells to that time. Bruce et al. (2000) confirmed that the G701D mutant protein has an absolute requirement for glycophorin A for movement to the cell surface.
In a female infant with severe anemia and hydrops, in whom renal tubular acidosis was detected by age 3 months, Ribeiro et al. (2000) identified homozygosity for a V488M mutation (109270.0022), which had previously been reported in association with spherocytosis in heterozygous state by Alloisio et al. (1997).
Sritippayawan et al. (2004) reported 2 Thai families with recessive dRTA due to different compound heterozygous mutations of the SLC4A1 gene. In the first family, the patient with dRTA had compound heterozygous G701D/S773P (109270.0026) mutations. In the second family, the patient and his sister had dRTA and SAO, and were compound heterozygotes for the SAO deletion mutation and an R602H mutation (109270.0027). Sritippayawan et al. (2004) noted that the second patient had a severe form of dRTA whereas his sister had only mild metabolic acidosis, indicating that other modifying factors or genes might play a role in governing the severity of the disease.
Kittanakom et al. (2004) transiently transfected human embryonic kidney HEK293 cells with the renal isoform of SLC4A1 containing the S773P mutation, alone or in combination with wildtype SLC4A1 or with the G701D mutant. The S773P mutant was expressed at a 3-fold lower level than wildtype, had a 2-fold decrease in its half-life, and was targeted for degradation by the proteasome. Both S773P and G701D exhibited defective trafficking to the plasma membrane, providing an explanation for the dysfunction found in dRTA.
Blood Groups
Diego blood group (110500) Di(a) is a low-incidence blood group antigen in Caucasians that is antithetical to Di(b). Prevalence of Di(a) is much higher in American Indians, reaching up to 54% in some groups of South American Indians. Bruce et al. (1994) demonstrated that the Diego blood group polymorphism is the result of a single amino acid substitution at position 854 of the AE1 molecule, with proline of the wildtype band 3 corresponding to the Di(b) antigen and leucine to the Di(a) antigen. Subsequently, Bruce et al. (1995) mapped the low-incidence blood group antigen Wr(a) (109270.0011) to the C-terminal end of the fourth ectoplasmic loop and defined a single amino acid substitution in Wr(b) (109270.0006). Jarolim et al. (1998) studied the molecular basis of 7 low-incidence blood group antigens that likewise are due to variation in AE1.
McManus et al. (2000) demonstrated that the Froese blood group polymorphism (601551) is the result of change in the SLC4A1 gene (109270.0029).
Zelinski et al. (2000) demonstrated that the Swann blood group (601550) is due to molecular changes in the SLC4A1 gene (109270.0030).
Inaba et al. (1996) studied a moderately uncompensated bovine anemia associated with spherocytosis inherited in an autosomal incompletely dominant mode and retarded growth. Using biochemical methods they showed that the bovine red cells lacked the band 3 protein completely. Sequence analysis of EPB3 cDNA and genomic DNA showed a C-to-T transition resulting in a missense mutation: CGA-to-TGA; arg646-to-ter. The location of the mutation was at the position corresponding to codon 646 in human EPB3 cDNA. The animal red cells were deficient in spectrin, ankyrin, actin (see 102630), and protein 4.2 (177070), resulting in a distorted and disrupted membrane skeletal network with decreased density. Therefore, the animal's red cell membranes were extremely unstable and showed the loss of surface area in several distinct ways such as invagination, vesiculation, and extrusion of microvesicles, leading to the formation of spherocytes. Inaba et al. (1996) also found that total deficiency of bovine band 3 also resulted in defective chloride/bicarbonate exchange, causing mild acidosis with decreases in bicarbonate concentration and total CO(2) in the animal's blood. The results demonstrated to the authors that bovine band 3 contributes to red cell membrane stability, CO(2) transport, and acid-base homeostasis, but is not always essential to the survival of this mammal.
Erythroid band 3 (AE1) is one of 3 anion exchanges that are encoded by separate genes. The AE1 gene is transcribed by 2 promoters: the upstream promoter is used for erythroid band 3, whereas the downstream promoter initiates transcription of the band 3 isoform in kidney. To assess the biologic consequences of band 3 deficiency, Southgate et al. (1996) selectively inactivated erythroid but not kidney band 3 by gene targeting in mice. Although no death in utero occurred, most homozygous mice died within 2 weeks after birth. The erythroid band 3-null mice showed retarded growth, spherocytic red blood cell morphology, and severe hemolytic anemia. Remarkably, the band 3 -/- red blood cells assembled normal membrane skeleton, thus challenging the notion that the presence of band 3 is required for stable biogenesis of the membrane skeleton. Similarly, Peters et al. (1996) used targeted mutagenesis in the mouse to assess AE1 function in vivo. RBCs lacking AE1 spontaneously shed membrane vesicles and tubules, leading to severe spherocytosis and hemolysis, but the levels of the major skeleton components, the synthesis of spectrin in mutant erythroblasts, and skeletal architecture were normal or nearly normal. Their results indicated that AE1 does not regulate RBC membrane skeleton assembly in vivo but is essential for membrane stability. Peters et al. (1996) postulated that stabilization is achieved through AE1-lipid interactions and that loss of these interactions is a key pathogenic event in hereditary spherocytosis. Jay (1996) reviewed the role of band 3 in red cell homeostasis and cell shape.
Paw et al. (2003) characterized a zebrafish mutant called retsina (ret) that exhibits an erythroid-specific defect in cell division with marked dyserythropoiesis similar to human congenital dyserythropoietic anemia (see 224100). Erythroblasts from ret fish show binuclearity and undergo apoptosis due to a failure in the completion of chromosome segregation and cytokinesis. Through positional cloning, Paw et al. (2003) demonstrated that the ret mutation is in the Slc4a1 gene, encoding the anion exchanger-1 (also called band 3 and AE1), an erythroid-specific cytoskeletal protein. They further showed an association between deficiency in Slc4a1 and mitotic defects in the mouse. Rescue experiments in ret zebrafish embryos expressing transgenic Slc4a1 with a variety of mutations showed that the requirement for band 3 in normal erythroid mitosis is mediated through its protein 4.1R-binding domains. Paw et al. (2003) concluded that their report established an evolutionarily conserved role for band 3 in erythroid-specific cell division and illustrated the concept of cell-specific adaptation for mitosis.
In addition to the variants of band 3 leading to abnormalities of erythrocyte shape (Liu et al., 1990), Mueller and Morrison (1977) identified a polymorphism tentatively described as an elongation of the cytoplasmic domain, whose structure was still to be defined. Ranney et al. (1990) found a silent band 3 polymorphism, called band 3 Memphis, in all human populations with a frequency varying from one population to another. Yannoukakos et al. (1991) demonstrated that this electrophoretic variant is due to substitution of glutamic acid for lysine at position 56. An A-to-G substitution in the first base of codon 56 is responsible for the change.
Ideguchi et al. (1992) showed that the prevalence of the Memphis variant is particularly high in Japanese; the calculated gene frequency was 0.156, about 4 times higher than in Caucasians. They found that the transport rate of phosphoenolpyruvate in erythrocytes of homozygotes was decreased to about 80% of that in control cells and the rate in heterozygotes was at an intermediate level. They interpreted this as indicating that some structural changes in the cytoplasmic domain of band 3 influence the conformation of the anion transport system. The band 3 Memphis variant is characterized by a reduced mobility of proteolytic fragments derived from the N-terminus of the cytoplasmic domain of band 3 (cdb3).
Jarolim et al. (1992) found the AAG-to-GAG transition at codon 56 resulting in the lys56-to-glu substitution in all of 12 heterozygotes including 1 white, 1 black, 1 Chinese, 1 Filipino, 1 Malay, and 7 Melanesian subjects. Since most of the previously cloned mouse, rat, and chicken band 3 and band 3-related proteins contain glutamic acid in the position corresponding to amino acid 56 in the human band 3, Jarolim et al. (1992) proposed that the Memphis variant is the evolutionarily older form of band 3.
The Memphis polymorphism is also referred to as rs5036. Wilder et al. (2009) found that all 4 Indonesian chromosomes with the 27-bp deletion (109270.0002) also carried the Memphis polymorphism, suggesting that it is a target of recent natural selection.
Following up on the demonstration by Liu et al. (1990) that a structurally and functionally abnormal band 3 protein shows absolute linkage with the SAO phenotype (166900), Jarolim et al. (1991) demonstrated that the EPB3 gene in these cases contains a 27-bp deletion, resulting in deletion of 9 amino acids (codons 400-408) in the boundary of cytoplasmic and membrane domains of the band 3 protein. The defect was detected in all 30 ovalocytic subjects from Malaysia, the Philippines, and 2 unrelated coastal regions of Papua New Guinea, whereas it was absent in all 30 controls from Southeast Asia and 20 subjects of different ethnic origin from the United States. The lys56-to-glu mutation (109270.0001) was also found in all SAO subjects; however, it was detected in 5 of 50 control subjects as well, suggesting that it represents a linked polymorphism.
Mohandas et al. (1992) likewise demonstrated the deletion of amino acids 400-408 in the boundary between the cytoplasmic and the first transmembrane domains of band 3. The biophysical consequences of the mutation was a marked decrease in lateral mobility of band 3 and an increase in membrane rigidity. Mohandas et al. (1992) suggested that the mutation induces a conformational change in the cytoplasmic domain of band 3, leading to its entanglement in the skeletal protein network. This entanglement inhibits the normal unwinding and stretching of the spectrin tetramers necessary for membrane extension, leading to increased rigidity.
The same deletion of 9 amino acids was found by Tanner et al. (1991) in a Mauritian Indian and by Ravindranath et al. (1994) in an African American mother and daughter. All cases of SAO had been associated with the Memphis-1 polymorphism (109270.0001), which is found in all populations but is present at higher frequency in American Indian and African American populations. However, SAO had not previously been identified in African Americans.
The band 3 deletion in Southeast Asian ovalocytosis may prevent cerebral malaria (611162), but it exacerbates malarial anemia and may also increase acidosis, a major determinant of mortality in malaria. Allen et al. (1999) undertook a case-control study of children admitted to hospital in a malarious area of Papua New Guinea. The 24-bp deletion, detected by PCR, was present in 0 of 68 children with cerebral malaria, compared with 6 (8.8%) of 68 matched community controls. Median hemoglobin levels were 1.2 g/dl lower in malaria cases with Southeast Asian ovalocytosis than in controls (P = 0.035), but acidosis was not affected. The band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The remarkable protection that the SAO variant affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium and the pathogenesis of cerebral malaria.
The abnormal SAO protein does not mediate chloride transport (Groves et al., 1993), and homozygosity for the 9-amino acid deletion is apparently lethal (Liu et al., 1994).
Yusoff et al. (2003) examined the incidence of SAO in Malays in Kelantan, Malaysia, who had distal renal tubular acidosis. SAO was identified in 18 of the 22 distal renal tubular acidosis patients (81.8%), but in only 2 of the 50 controls (4%). Yusoff et al. (2003) referred to the band 3 variant as a 27-nt deletion.
In a population-based study of 19 individuals each from Japan, Taiwan, and Indonesia, Wilder et al. (2009) found the 27-bp deletion associated with the SAO trait in 4 of the Indonesian samples only. These 4 SAO chromosomes also carried the Memphis variant (109270.0001). The haplotype associated with the 27-bp deletion was also found in Japanese samples, but not in Taiwanese samples, which was a surprising finding since Taiwan was thought to be part of the Austronesian population expansion. The findings indicated that chromosomes related to Indonesian SAO alleles are not a major component of genetic diversity among aboriginal Taiwanese, and suggested that the SLC4A1 gene is subject to natural selection.
Jarolim et al. (1991) studied a 28-year-old black female with congenital spherocytic hemolytic anemia (SPH4; 612653). Splenectomy corrected the anemia but only partially normalized the reticulocyte count. Although there was partial deficiency of protein 4.2 (177070), other findings suggested a primary defect in band 3. By study of a PCR-amplified cDNA segment from the EPB3 gene, Jarolim et al. (1991) demonstrated a CCC-to-CGC transversion converting pro327 to arginine. Proline-327 is located in a highly conserved region of band 3 and its substitution by the basic arginine was expected to change both the secondary and tertiary structure of the cytoplasmic domain of band 3. The same allele carried a lys56-to-glu substitution, a common asymptomatic polymorphism designated band 3 Memphis (109270.0001). Direct sequencing of genomic DNA from the patient's unaffected mother and 2 sibs revealed neither of the 2 substitutions. Thus, the patient presumably represented a new mutation.
In a 33-year-old female with episodes of clinically apparent hemolytic anemia coincident with pregnancies and associated with splenomegaly and spherocytosis (SPH4; 612653), Rybicki et al. (1993) found a glu40-to-lys mutation in the cytoplasmic domain of the EPB3 gene. The mutation was homozygous; the proposita was the offspring of first-cousin parents born in the Dominican Republic, largely of Spanish origin with some black admixture. A striking feature was decreased RBC membrane content of protein 4.2 (177070) which was thought to be a secondary phenomenon resulting from defective interactions with band 3.
Jarolim et al. (1994) described duplication of 10 nucleotides (2455-2464) in the EPB3 gene in a family from Prague, Czech Republic, with 5 individuals affected by spherocytosis (SPH4; 612653) in 3 generations. Before splenectomy, the affected subjects had a compensated hemolytic disease with reticulocytosis, hyperbilirubinemia, and increased osmotic fragility. There was a partial deficiency of the band 3 protein that was reflected by decreased rate of transmembrane sulfate flux and decreased density of intramembrane particles. The mutant allele potentially encoded an abnormal band 3 protein with a 3.5-kD COOH-terminal truncation; however, they did not detect the mutant protein in the membrane of mature red blood cells. Since the mRNA levels for the mutant and normal alleles were similar and since the band 3 content was the same in the light and dense red cell fractions, Jarolim et al. (1994) concluded that the mutant band 3 was either not inserted into the plasma membrane or was lost from the membrane before release of red cells into the circulation.
Bruce et al. (1995) demonstrated that the blood group Wright antigens (112050) are determined by mutation at amino acid residue 658 of erythrocyte band-3.
In a large Swiss family with dominantly inherited spherocytosis and deficiency of band-3 (SPH4; 612653), previously reported by Reinhart et al. (1994), Maillet et al. (1995) demonstrated a gly771-to-asp (G771D) (GGC-to-GAC) mutation in the EPB3 gene by single-strand conformation polymorphism analysis and nucleotide sequencing. The mutation was present in all 8 affected members of the family studied and was absent in 4 healthy members. The mutation was located at a highly conserved position in the middle of transmembrane segment 11, introducing a negative charge in a stretch of 16 apolar or neutral residues.
In a French kindred with typical autosomal dominant hereditary spherocytosis (SPH4; 612653), Jenkins et al. (1996) found a 15 to 20% deficiency of band-3, as well as abnormal erythrocyte membrane mechanical stability. Anion transport studies of red cells from 2 affected individuals demonstrated decreased sulfate flux. A sequence analysis of genomic DNA demonstrated a nonsense mutation of the EPB3 gene, gln330 to ter (Q330X), near the end of the band-3 cytoplasmic domain. The mutation was present in genomic DNA of all HS family members and absent in DNA of all unaffected family members. The variant was named band-3 Noirterre after the village of residence of the family in France. The change in codon 330 was from CAG to TAG.
Alloisio et al. (1996) described an 18-year-old man with moderate hereditary spherocytosis (SPH4; 612653). The condition was associated with a 35% decrease in erythrocyte band-3. The underlying mutation was arg150 to ter (R150X) due to a CGA-to-TGA transition in codon 150. They designated the new allele band-3 Lyon. The inheritance was dominant; however, the mother, who also carried the allele Lyon, had a milder clinical presentation and only a 16% decrease of band-3. They suspected the father had transmitted a modifying mutation that remained silent in the heterozygous state in him. Nucleotide sequencing after SSCP analysis of the band-3 cDNA and promoter region revealed a G-to-A substitution at position 89 from the cap site in the 5-prime untranslated region of the EPB3 gene (designated 89G-to-A), an allele they referred to as band-3 Genas (109270.0010). A ribonuclease protection assay showed that (1) the allele Genas from the father resulted in a 33% decrease in the amount of band-3 mRNA; (2) the reduction caused by the allele Lyon (mother) was 42%; and (3) the compound heterozygous state for both alleles (proband) resulted in a 58% decrease. These results suggested that some mildly deleterious alleles of the EPB3 gene are compensated for by the normal allele in the heterozygous state. They become manifest, however, through the aggravation of the clinical picture, based on molecular alterations when they occur in 'trans' to an allele causing a manifest reduction of band-3 membrane protein concentration.
See 109270.0009 and Alloisio et al. (1996).
Bruce et al. (1995) demonstrated that the low-incidence blood group antigen Wd(a) (112010) is associated with a val557-to-met substitution in erythrocyte band-3.
Bruce et al. (1997) found an arg589-to-his mutation in affected members of 2 Irish families with autosomal dominant distal renal tubular acidosis (DRTA1; 179800). The same mutation was on a different haplotype in the 2 families. These families had previously been reported in part by Richards and Wrong (1972) and Wrong et al. (1993). The same arg589-to-his mutation was found in a sporadic case of distal RTA by Karet et al. (1998). The mutation was absent in both parents and the unaffected sibs of the index case.
In a family with autosomal dominant distal renal tubular acidosis (DRTA1; 179800), Bruce et al. (1997) found an arg589-to-cys mutation in the SLC4A1 gene.
In a family with autosomal dominant distal renal tubular acidosis (DRTA1; 179800), Bruce et al. (1997) found a ser613-to-phe mutation in the SLC4A1 gene.
In a family with autosomal dominant distal renal tubular acidosis (DRTA1; 179800), Karet et al. (1998) found an arg589-to-ser mutation in the SLC4A1 gene. This was the third substitution in the arg589 codon to be identified as the cause of dominant distal RTA. In this family, RTA was diagnosed in 2 women because of nephrolithiasis at ages 56 and 36 years. Prospective screening identified other affected family members who were all asymptomatic.
Tanphaichitr et al. (1998) described homozygosity for a gly701-to-asp (G701D) loss-of-function mutation in the SLC4A1 gene in a Thai brother and sister with autosomal recessive distal RTA and hemolytic anemia (DRTA4; 611590). The male proband presented at age 3.5 years with a history of lethargy, anorexia, and slow growth. Physical examination showed height and weight less than the third percentile, pallor, and hepatosplenomegaly. Hypokalemia, hyperchloremic metabolic acidosis, and normal creatinine were accompanied by isosthenuria and alkaline urinary pH, bilateral nephrocalcinosis, and rachitic bone changes. Mild anemia (hematocrit 11 g/dl) with microcytosis, reticulocytosis, and a peripheral smear consistent with a xerocytic type of hemolytic anemia were accompanied by homozygosity for hemoglobin E, a clinically benign hemoglobin frequently encountered in Southeast Asia. The sister showed similar findings.
Bruce et al. (2000) found the G701D mutation as 1 of 3 associated with distal renal tubular acidosis and hemolytic anemia in families from Malaysia and Papua New Guinea. The other 2 mutations were ala858 to asp (A858D; 109270.0020) and deletion of val850 (delV850; 109270.0021).
Yenchitsomanus et al. (2002) found that all Thai patients with autosomal recessive distal RTA caused by homozygosity for the G701D mutation originated from northeastern Thailand. Yenchitsomanus et al. (2003) confirmed the higher allele frequency of the G701D mutation in this population. This suggested that the G701D allele might have arisen in northeastern Thailand. The presence of patients with distal RTA who were compound heterozygotes for the Southeast Asian ovalocytosis mutation (109270.0002) and G701D in southern Thailand and Malaysia and their apparent absence in northeastern Thailand indicated that the G701D allele may have migrated to the southern peninsula region where SAO is common, resulting in pathogenic allelic interaction.
Bruce et al. (1994) demonstrated that the blood group Diego antigens (110500) Di(a) and Di(b) are determined by a single amino acid substitution at position 854 of the SLC4A1 gene, with proline corresponding to the Di(b) antigen and leucine to the Di(a) antigen.
Inoue et al. (1998) described a Japanese family with hereditary spherocytosis (SPH4; 612653) associated with a homozygous missense mutation of the band-3 gene, gly130 to arg. The homozygous unsplenectomized proband was a 29-year-old male with compensated hemolytic anemia.
Iwase et al. (1998) reported the case of a 22-year-old Japanese man who was admitted to hospital with cholelithiasis and hemolysis. He had been icteric since early childhood. SDS-PAGE of erythrocyte membrane proteins showed that the patient's band-3 was reduced to about 80% of the control level. Molecular analysis demonstrated a change of codon 837 from ACG (thr) to GCG (ala) in the AE1 gene. In bone marrow mononuclear cells, both mutant and wildtype mRNA were comparably detected, suggesting that this mutation interfered with band-3 processing or assembly, leading to impaired accumulation of mutant band-3 in the plasma membrane. There was no history suggesting other cases in the family; this appeared to be an instance of heritable spherocytosis, but not hereditary spherocytosis.
Bruce et al. (2000) identified an ala858-to-asp mutation of the SLC4A1 gene as the cause of autosomal dominant renal tubular acidosis (179800) in families in Malaysia and Papua New Guinea. Red cells with compound heterozygosity for A858D and the Southeast Asian ovalocytosis mutation (109270.0002) had the lowest anion transport activity reported for human red cells to that time. Bruce et al. (2000) suggested that the dominant A858D mutant protein is possibly mistargeted to an inappropriate plasma membrane domain in the renal tubular cell.
Bruce et al. (2000) observed autosomal recessive renal tubular acidosis with hemolytic anemia (DRTA4; 611590) due to deletion of valine-850 of the SLC4A1 gene in families from Malaysia and Papua New Guinea. In combination with the Southeast Asian ovalocytosis mutation (109270.0002), the renal tubular acidosis displayed a pseudodominant pedigree pattern. Bruce et al. (2000) suggested that the recessive delV850 mutation may give rise to dRTA because of its decreased anion transport activity in the kidney.
In the heterozygous state, band-3 Coimbra causes typical hereditary spherocytosis (SPH4; 612653) and is associated with partial deficiency of band-3 and, as a secondary phenomenon, of protein 4.2 (177070) (Alloisio et al., 1997). Band 3 Coimbra is caused by a GTG-to-ATG change in exon 13 of the SLC4A1 gene, resulting in a val488-to-met substitution.
Ribeiro et al. (2000) reported severe hereditary spherocytosis and renal tubular acidosis (DRTA4; 611590) associated with total absence of band-3 in an infant homozygous for the Coimbra mutation. Because the fetus stopped moving near term, an emergency cesarean section was performed and a severely anemic, hydropic female baby was delivered. She was resuscitated and initially kept alive with respiratory assistance and hypertransfusion therapy. Band 3 and protein 4.2 were absent; spectrin, ankyrin, and glycophorin A were significantly reduced. Renal tubular acidosis was detected by the age of 3 months. Nephrocalcinosis appeared soon thereafter. With regular blood transfusions and daily bicarbonate supplements, the child was doing 'reasonably well' at the age of 3 years.
Bracher et al. (2001) described a child with severe spherocytosis (SPH4; 612653) who was compound heterozygous for 2 defects of band-3: a novel GAG-to-AAG point mutation in exon 5, resulting in a glu90-to-lys (E90K) substitution, which they designated band-3 Cape Town, and, in trans, a previously described mutation, band-3 Prague III (109270.0024). The patient was a Cape Coloured female child who presented at the age of 17 months.
Bracher et al. (2001) described a case of severe spherocytosis (SPH4; 612653) due to compound heterozygosity for an E90K mutation (109270.0023) and the CGG-to-TGG band-3 Prague III mutation in exon 19 of the SLC4A1 gene, arg870 to trp (R870W), previously described by Jarolim et al. (1995). The mother had a normal blood count, osmotic fragility, and peripheral blood smear; the father was unknown. The child displayed no jaundice and did not have splenomegaly.
Toye et al. (2002) reported studies of band-3 Walton, a C-terminal deletion associated with distal renal tubular acidosis (DRTA1; 179800), in 2 brothers (Karet et al., 1998). The insertion-deletion underlying band-3 Walton consisted of a 13-bp insertion after the first base of amino acid 900 in exon 20. In addition, deletion of 9 bp over the sequence that would have coded for amino acids tyr904 to glu906 of normal band-3 was also present. The net effect was a premature stop codon and deletion of the 11 COOH-terminal amino acids of the protein. The brothers were heterozygous for the mutation. They had thirst, polyuria, and occasional renal colic since childhood and were diagnosed as having distal renal tubular acidosis on the basis of acidosis and hypokalemia at ages 37 and 25 years, respectively. Red cell morphology was normal, but both patients had a tendency to erythremia, a recognized complication of nephrocalcinosis from various causes (Feest et al., 1978). The parents were dead, and there were no known living relatives for study. Toye et al. (2002) demonstrated that the band-3 Walton protein is expressed in the red cell membrane but retained internally in kidney cells.
Quilty et al. (2002) examined the effect of the 11-amino acid C-terminal deletion, which they called 901-stop, on the biosynthesis, folding, and trafficking of AE1 in transfected human embryonic kidney cells. The 901-stop mutation did not effect the folding of AE1, but it did alter its trafficking to the plasma membrane. Coexpression of wildtype and mutant proteins, mimicking the heterozygous state of the patients carrying the mutation (Karet et al., 1998), resulted in heterooligomer formation and impaired trafficking of the wildtype protein to the medial Golgi. Quilty et al. (2002) concluded that the altered trafficking of the mutant protein and its dominant-negative effect could explain both its effect on urine acidification and its dominant inheritance pattern.
In a Thai patient with dRTA and normal red cell morphology (see 611590), Sritippayawan et al. (2004) identified compound heterozygosity for the G701D (109270.0016) mutation and a T-to-C transition in exon 18 of the SLC4A1 gene, resulting in a ser773-to-pro (S773P) substitution. The patient's clinically normal mother and father were heterozygous for these mutations, respectively.
In a Thai brother and sister with dRTA and Southeast Asian ovalocytosis (SAO) (see DRTA4; 611590), Sritippayawan et al. (2004) identified compound heterozygosity for the SAO deletion mutation (109270.0002) and a G-to-A transition in exon 15, resulting in an arg602-to-pro (R602P) substitution. Their mother had SAO and an unaffected brother was heterozygous for the R602P mutation. The patient had a severe form of dRTA whereas his sister had only mild metabolic acidosis, indicating that other modifying factors or genes might play a role in governing the severity of the disease.
Jarolim et al. (1995) identified an arg760-to-gln (R760Q) substitution in the band 3 gene, designated band 3 Prague II, in 2 patients with hereditary spherocytosis (SPH4; 612653).
In 2 families with SPH4 that were previously reported by Gore et al. (2002), Bruce et al. (2005) identified heterozygosity for a 2279G-A transition in exon 17 of the SLC4A1 gene, resulting in the R760Q substitution at a highly conserved residue. Expression of R760Q in Xenopus laevis oocytes induced abnormal sodium and potassium fluxes, and induced chloride transport was low, suggesting that the substitution converts the protein from an anion exchanger into an unregulated cation channel.
McManus et al. (2000) demonstrated that the Froese blood group polymorphism is due to a missense mutation glu480-to-lys (E480K) in RBC band-3.
Zelinski et al. (2000) demonstrated that DNA from Sw(a+) (601550) individuals showed one or the other of 2 mutations in exon 16 of the SLC4A1 gene, CGG to CAG or CGG to TGG, resulting in an arg646-to-gln or arg646-to-trp substitution, respectively.
See 109270.0030 and Zelinski et al. (2000).
In 1 of the 2 sibs with acanthocytosis and increased anion transport activity of red cells, originally described by Kay et al. (1987, 1988), Bruce et al. (1993) identified a pro868-to-leu (P868L) substitution in the putative last membrane-spanning segment of the SLC4A1 protein. They designated this mutation band 3 HT (high transport). The red cells of the parents of the sibs also showed increased anion transport, but the V(max) was not increased to the same degree as in the affected children, suggesting that the children were homozygous for the mutation (Kay et al., 1988).
In affected members of 4 unrelated families with cryohydrocytosis (CHC; 185020), including 2 families originally reported by Coles et al. (1999) and 1 family previously reported by Haines et al. (2001) (family C), Bruce et al. (2005) identified heterozygosity for a c.2191T-C transition in exon 17 of the SLC4A1 gene, resulting in a ser731-to-pro (S731P) substitution at a highly conserved residue. The mutation segregated fully with disease in each family and was not found in 76 controls. Expression of S731P in Xenopus laevis oocytes induced abnormal sodium and potassium fluxes, and induced chloride transport was low, suggesting that the substitution converts the protein from an anion exchanger into an unregulated cation channel. Bruce et al. (2005) proposed the designation 'band 3 Hemel' for the S731P mutation.
In affected members of a family with cryohydrocytosis (CHC; 185020), originally reported by Haines et al. (2001) (family D), and a male patient from Zurich who was the sole affected member of his family, Bruce et al. (2005) identified heterozygosity for a c.2201A-G transition in exon 17 of the SLC4A1 gene, resulting in a his734-to-arg (H734R) substitution at a highly conserved residue. The mutation segregated fully with disease in both families and was not found in 76 controls. Expression of H734R in Xenopus laevis oocytes induced abnormal sodium and potassium fluxes, and induced chloride transport was low, suggesting that the substitution converts the protein from an anion exchanger into an unregulated cation channel. Two other heterozygous SLC4A1 variants were detected in the proband of family D: a silent mutation (L417L) and the band 3 Memphis polymorphism (109270.0001). Bruce et al. (2005) proposed the designation 'band 3 Hurstpierpoint' for the H734R mutation.
In 2 unrelated families with cryohydrocytosis (CHC; 185020) and a 'shallow slope' pattern of temperature-dependent potassium flux, Bruce et al. (2005) identified heterozygosity for a c.2060T-C transition in exon 17 of the SLC4A1 gene, resulting in a leu687-to-pro (L687P) substitution at a highly conserved residue. The mutation segregated fully with disease in both families and was not found in 76 controls. Expression of L687P in Xenopus laevis oocytes induced abnormal sodium and potassium fluxes, and induced chloride transport was low, suggesting that the substitution converts the protein from an anion exchanger into an unregulated cation channel. One of the families ('Blackburn') was originally reported by Alani et al. (1994) as an example of hereditary spherocytosis associated with pseudohyperkalemia; reexamination by Coles et al. (1999) revealed stomatocytes on the blood film. Affected members exhibited a mild hemolytic anemia associated with marked pseudohyperkalemia. The other family, originally reported by Gore et al. (2004) ('Darlington'), also had previously been given a diagnosis of 'atypical spherocytosis,' but the proband had 5 to 10% stomatocytes on blood film and showed pseudohyperkalemia. Bruce et al. (2005) proposed the designation 'band 3 Blackburn' for the L687P mutation.
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