Band 3 anion transport protein (SLC4A1)

The protein contains 911 amino acids for an estimated molecular weight of 101792 Da.

 

Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Major integral membrane glycoprotein of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine. (updated: March 4, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.


Interpro domains
Total structural coverage: 42%
Model score: 44

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VariantDescription
empty
dbSNP:rs5035
Found in patients with hemolytic anemia
dbSNP:rs34700496
Di(a)/Memphis-II antigen
dbSNP:rs13306787
dbSNP:rs13306788
dbSNP:rs781490287
SPH4
dbSNP:rs5037
SPH4
SPH4; Mondego
SPH4; Boston
SPH4
NFLD+ antigen
ELO antigen
dbSNP:rs5018
SPH4; Benesov
SPH4; Yamagata
FR(a+) antigen
SPH4
SPH4
SPH4
dbSNP:rs45568837
SPH4
RB(A) antigen
TR(A) antigen
WARR antigen
VG(a) antigen
WD(a) antigen
NFLD+ antigen
BOW antigen
WU antigen
KREP antigen
PN(a) antigen
BP(a) antigen
dbSNP:rs5019
AD-dRTA
AD-dRTA
AD-dRTA
dRTA-HA
AD-dRTA
AD-dRTA
SW(a+) antigen
SW(a+) antigen
HG(a) antigen
MO(a) antigen
WR(a) antigen
SPH4; Tambau
CHC
dbSNP:rs5022
dbSNP:rs5023
dRTA-HA and dRTA-NRC
SPH4; Horam; induces abnormal cations sodium and potassium fluxes; decreases anion chloride transport
SPH4; Most
SPH4; Okinawa
CHC
CHC
SPH4
SPH4
SPH4
dRTA-NRC
SPH4; Napoli II
SPH4
SPH4
dbSNP:rs5025
SPH4; Birmingham
SPH4
SPH4; Philadelphia
SPH4; Nagoya
Di(a)/Memphis-II antigen
AD-dRTA
dbSNP:rs5026
acanthocytosis
SPH4

The reference OMIM entry for this protein is 109270

Solute carrier family 4 (anion exchanger), member 1; slc4a1
Band 3 of red cell membrane; bnd3
Erythrocyte membrane protein band 3; empb3
Erythroid protein band 3; epb3
Anion exchange protein 1; ae1 acanthocytosis, one form of, included
Oval

DESCRIPTION

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 (reviewed by Palumbo et al., 1986).

CLONING

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.

GENE FUNCTION

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. ... More on the omim web site

The reference OMIM entry for this protein is 110500

Blood group--diego system; di
Diego blood group

A number sign (#) is used with this entry because of evidence that the blood group antigens of the Diego system are caused by a single amino acid variation in the SLC4A1 gene (109270), which encodes the erythrocyte band-3 protein. The Diego blood group system is controlled by 2 allelic genes: Di(a) and Di(b). The Di(a) antigen was first described in Venezuela on the basis of an antibody that had been the cause of hemolytic disease of the newborn (Levine et al., 1956). A second example of anti-Di(a) was found in Buffalo in the serum of a Polish mother, whose child also suffered from hemolytic disease of the newborn (Tatarsky et al., 1959). The Diego system shows polymorphism mainly in Mongolian peoples, e.g., Chinese and American Indians. In a family of Polish origin, Kusnierz-Alejska and Bochenek (1992) found anti-Di(a) antibody in the serum of a mother who gave birth to a newborn with severe hemolytic anemia. They identified the Di(a) antigen in 45 of 9,661 donor blood samples from different regions of Poland (0.46%). All 45 were of Polish ancestry. Zelinski et al. (1993) showed that the DI blood group is tightly linked to the erythrocyte surface protein band-3 locus (SLC4A1); maximum lod = 5.42 at theta = 0.00. Looser linkage between DI and D17S41 (maximum lod = 3.14 at theta = 0.09) for combined paternal and maternal meioses was also established. The EPB3 gene is located at 17q21-q22. Indeed, Bruce et al. (1994) demonstrated that the Di(a)/Di(b) polymorphism is a single amino acid substitution at position 854 of the band-3 protein, with proline of the wildtype band-3 protein corresponding to the Di(b) antigen and leucine to the Di(a) antigen (109270.0017). Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). ... More on the omim web site

The reference OMIM entry for this protein is 601551

Blood group--froese
Fr
Froese blood group antigen

A number sign (#) is used with this entry because of evidence that the low-incidence Froese blood group antigen polymorphism is based on a change in the SLC4A1 (109270) gene, which encodes erythrocyte protein band-3, on chromosome 17q21.

DESCRIPTION

The low-incidence red cell antigen Fr(a) was described by Lewis et al. (1978) in Mennonite kindreds in Manitoba. It was shown to be inherited as an autosomal dominant trait, and although it was not very polymorphic in the general population, it was studied in sizable kindreds.

MAPPING

Genetic linkage excluded the FR locus from 17 of the 23 established blood group systems (Daniels et al., 1995). Another private blood group antigen, Wd(a), which defines the Waldner blood group locus (WD; 112010) was shown to map to 17q and to a point mutation in the SLC4A1 gene (109270). Zelinski et al. (1996) showed that the FR locus is tightly linked to SLC4A1 with a peak lod score of 5.72 in 5 nuclear families from 3 previously unpublished Mennonite kindreds. The Swann blood group locus (SW; 601550) and the WD and FR loci all mapped to the 17q12-q24 region, suggesting that they may represent separate alleles of the SLC4A1 gene.

MOLECULAR GENETICS

In 2 unrelated Mennonite kindreds segregating for Fr(a), McManus et al. (2000) demonstrated an SLC4A1 exon 13 mobility shift in the SSCP analysis in the DNA from all Fr(a+) persons that was not seen in the DNA from Fr(a-) family members or control subjects. Linkage between the exon 13 SSCP and Fr(a) was established, with peak lods of 3.62 at theta = 0.00 for combined paternal and maternal meioses. DNA sequencing revealed a GAG-to-AAG mutation that underlies a glu480-to-lys substitution in erythrocyte protein band 3. McManus et al. (2000) defined Fr(a) as a Diego system (110500) member. On the basis of erythrocyte band-3 structural predictions, they concluded that the glu480-to-lys substitution is located in the second extracellular loop of the protein; thus, Fr(a) was the first antigen to be localized to this region of the molecule. ... More on the omim web site

The reference OMIM entry for this protein is 601550

Blood group--swann system; sw
Swann blood group

A number sign (#) is used with this entry because of evidence that the Swann blood group antigens result from variation in the SLC4A1 gene (109270), which encodes the erythrocyte band-3 protein, on chromosome 17q21.

DESCRIPTION

The low-incidence red cell antigen Sw(a) of the Swann blood group system was described by Cleghorn (1959). It was shown to be inherited as an autosomal dominant trait and, although it was not very polymorphic in the general population, sizable kindreds segregating for the SW locus were identified (Lewis et al., 1988).

MAPPING

Genetic linkage studies excluded SW from 17 of the 23 established blood group systems (Daniels et al., 1995). Zelinski et al. (1996) found a peak lod score of 3.01 for the linkage of SW and D17S41, a RFLP polymorphism on chromosome 17. No evidence of recombination was found. Families studied were 3 nuclear families from a previously described French Canadian kindred (Lewis et al., 1988). The SW locus is in the same region of 17q as the Waldner group locus (WD; 112010) and the Froese blood group locus (FR; 601551); although each resides within the 17q12-q24 region, each is clearly unique. Zelinski et al. (1996) showed that the FR locus is tightly linked to the SLC4A1 gene, where mutations causing the Waldner polymorphism are known to be located. They suggested that Fr(a) and Sw(a) may be due to mutations in the SLC4A1 gene.

MOLECULAR GENETICS

Molecular analysis demonstrating that Fr(a) and Sw(a) are caused by mutation in the SLC4A1 gene was provided by McManus et al. (2000) and by Zelinski et al. (2000), respectively; see 109270.0029 and 109270.0030. ... More on the omim web site

The reference OMIM entry for this protein is 112010

Blood group--waldner type; wd
Waldner blood group antigen

A number sign (#) is used with this entry because of evidence that Waldner blood group expression is caused by a point mutation in the SLC4A1 gene (109270). Lewis and Kaita (1981) found a 'new' red cell antigen in Hutterites of the surname Waldner. Zelinski et al. (1995) stated that the WD blood group antigen had been identified in Khoisans in South Africa and in a family in Holland. By genetic linkage analysis, they showed that WD is loosely linked to the reference marker D17S41 at 17q12-q24 and closely linked to the SLC4A1 locus at 17q12-q21. Bruce et al. (1995) demonstrated that the Wd(a) results from a substitution of methionine for valine-557 in erythrocyte band-3 (109270.0011). ... More on the omim web site

The reference OMIM entry for this protein is 112050

Blood group--wright antigen; wr
Wright blood group antigen

A number sign (#) is used with this entry because of evidence that the blood group Wright antigens are associated with a polymorphism in human erythrocyte band-3 (SLC4A1; 109270). The Wright antigen, a 'private' blood group (see 111500), was found by Holman (1953). Although it is very rare, the early date of its discovery and the ready availability of testing sera led to a large number of persons and variety of populations being tested. The frequency of the gene for the Wr(a) antigen was found to be about 3 in 10,000 among Europeans (Mourant et al., 1978). Because the Wr(b) antigen appeared to involve both red blood cell band-3 and glycophorin A (GPA; 111300), Bruce et al. (1995) examined the cDNA sequences of band-3 and GPA of 1 of the 2 known Wr(a+b-) individuals. They showed that this person was homozygous for a glu658-to-lys mutation in the BND3 gene, but had normal GPA. Putative heterozygotes with Wr(a+b+) RBCs had both glu and lys at residue 658 of band-3, whereas the common Wr(a-b+) RBC phenotype had only band-3 with glu658. Thus, the Wr(a) and Wr(b) antigens are determined by the amino acid at residue 658 of band-3 (109270.0006) and are antithetical. Bruce et al. (1995) proposed that arg61 of GPA interacts with glu658 of band-3 to form the Wr(b) antigen. ... More on the omim web site

The reference OMIM entry for this protein is 130600

Elliptocytosis 2; el2
Elliptocytosis, rhesus-unlinked type

A number sign (#) is used with this entry because of evidence that elliptocytosis-2 is caused by heterozygous mutation in the alpha-spectrin gene (SPTA1; 182860) on chromosome 1q23. For a general description and a discussion of genetic heterogeneity of elliptocytosis (HE), see EL1 (611804).

CLINICAL FEATURES

In some families with HE, spectrin is abnormally heat-sensitive (Lux and Wolfe, 1980). Coetzer and Zail (1981) studied spectrin in 4 cases of hereditary elliptocytosis and found an abnormality of tryptic digestion in 1. This patient was previously reported by Gomperts et al. (1973) as an instance of hemolytic anemia due to HE. Liu et al. (1982) examined erythrocytes from 18 patients with hereditary elliptocytosis. In 8 patients (referred to as type 1), spectrin was defective in dimer-dimer association as demonstrated in 2 ways. First, spectrin dimer was increased and tetramer decreased; spectrin dimer represented 15 to 33% of total spectrin compared with a normal range of 3 to 7%. Second, the equilibrium constants of spectrin dimer-dimer association was decreased in both solution and in situ in red cell membranes. In the other 10 patients (referred to as type 2), dimer-dimer association was normal. Membrane skeletons, produced from both types of elliptocytosis by Triton X-100 extraction of the red cell ghosts, were unstable when mechanically shaken. Spectrin tetramers but not dimers can crosslink actin. Evans et al. (1983) studied a family in which 3 sibs had severe transfusion-dependent, presumably homozygous elliptocytosis and both parents had asymptomatic elliptocytosis. Red cell membranes of all 3 sibs showed an excess of spectrin dimers over tetramers in spectrin extracts. Both parents showed an intermediate increase in spectrin dimers. In 7 black patients (from 5 unrelated families) with mild HE, Lecomte et al. (1985) found an abnormal thermal sensitivity and an important defect of spectrin dimer self-association. An excess of spectrin dimer and deficient dimer-to-tetramer conversion were demonstrated. Peptide patterns of crude spectrin showed a marked decrease in the 80-kD peptide (previously identified as the dimer-dimer interaction domain of the alpha chain) and a concomitant appearance of a novel 65-kD peptide. Anti-alpha-spectrin antibodies showed that the latter peptide was derived from the alpha chain. The patients were 3 unrelated adults, 2 children with hemolytic anemia, and the father of each child. Lawler et al. (1984, 1985) described a molecular defect in the alpha subunit of spectrin in a subset of patients with hereditary elliptocytosis; the self-association of alpha-beta heterodimers to form tetramers was defective. Abnormality of alpha spectrin was reported by Ravindranath and Johnson (1985) in a case of congenital hemolytic anemia. Lambert and Zail (1987) also found a variant of the alpha subunit. Two brothers with the poikilocytic variant of hereditary elliptocytosis were found to have a defect in spectrin dimer association and a decreased spectrin/band 3 ratio. The major abnormal tryptic peptides derived from the alpha-I domain had lower molecular weights and more basic isoelectric points than hitherto described. The propositus of Lambert and Zail (1987) was a black South African miner. In a 6-week-old black infant, Garbarz et al. (1986) found hemolytic anemia with red cell fragmentation, poikilocytosis, and elliptocytosis. Both parents and a brother of the propositus had compensated mild heredita ... More on the omim web site

The reference OMIM entry for this protein is 166900

Ovalocytosis, southeast asian; sao
Ovalocytosis, malaysian-melanesian-filipino type
Elliptocytosis 4; el4
Elliptocytosis, stomatocytic hereditary
He, stomatocytic

A number sign (#) is used with this entry because Southeast Asian ovalocytosis (SAO) is caused by a heterozyous 27-bp deletion in the SLC4A1 gene (109270) on chromosome 17q21.

DESCRIPTION

Southeast Asian ovalocytosis is a hereditary red blood cell disorder that is widespread in certain ethnic groups of Malaysia, Papua New Guinea, the Philippines, and Indonesia. Ovalocytic erythrocytes are rigid and exhibit reduced expression of many erythrocyte antigens. The ovalocytes are resistant to invasion in vitro by several strains of malaria, including Plasmodium falciparum and Plasmodium knowlesi (summary by Jarolim et al., 1991). The disorder is most often asymptomatic but has been reported to be associated with signs of mild hemolysis such as intermittent jaundice and gallstones (summary by Reardon et al., 1993).

CLINICAL FEATURES

Lie-Injo (1965) first pointed out the high frequency of ovalocytosis in studies of Malaysian Orang Asli. Lie-Injo et al. (1972), Ganesan et al. (1975), and Baer et al. (1976) extended the observations in Malaysia, where frequencies as high as 39% were found. Ganesan et al. (1975) reported an extraordinarily high frequency of ovalocytosis among the Land Dayaks (12.7%) and Sea Dayaks (9.0%), the indigenous people of Sarawak. Amato and Booth (1977), Booth et al. (1977), and Holt et al. (1981) identified another focus of high frequency of elliptocytosis in Melanesia (Papua New Guinea, Sarawak). The morphologic change in the red cells was apparently responsible for a previously described depression of blood group antigens (Booth, 1972), e.g., Gerbich blood group (616089), which was thought to be recessively inherited. Red cells in this condition are ovalocytes, which are often macrocytic; some, called stomatocytes, have a longitudinal slit in the middle. Indeed, stomatocytic hereditary elliptocytosis, or stomatocytic HE, is a synonym. 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). This may be a mutation of a structural protein of the red cell that endows the bearer with a selective 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. 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. Liu et al. (1990) found a structurally and functionally abnormal band 3 protein in Southeast Asian ovalocytosis. The abnormal protein binds tightly to ankyrin, thus leading to increased rigidity of the red cells, and in some way is responsible for the resistance of the red cells to invasion by malaria parasites. Jones et al. (1990) concluded that the markedly increased phosphorylation of band 3 protein in whole red cells or isolated ghosts from ovalocytic individuals might be explained by the following findings. The cytoplasmic domain of the ovalocyte band 3 was found to be approximately 3 kD larger than the normocytic protein. The N-terminal sequence of the ovalocytic band 3 was different from the reported sequence, suggesting that the increased size resulted ... More on the omim web site

The reference OMIM entry for this protein is 179800

Renal tubular acidosis, distal, autosomal dominant
Rta, distal type, autosomal dominant
Renal tubular acidosis i
Rta, classic type
Rta, gradient type

A number sign (#) is used with this entry because autosomal dominant distal renal tubular acidosis has been found to be caused by mutation in the SLC4A1 gene (109270).

CLINICAL FEATURES

Randall and Targgart (1961) observed renal tubular acidosis in members of several successive generations. All affected members showed both acidosis and nephrocalcinosis. Randall (1967) provided follow-up of this family. The pedigree included 4 instances of male-to-male transmission. The features were nephrocalcinosis, fixed urinary specific gravity, fixed urinary pH of about 5.0, high serum chloride, low serum bicarbonate, osteomalacia, and hypocalcemia. Alkalinization was effective therapy. Seedat (1968) observed 18 affected persons in 3 generations. In the well-studied family reported by Gyory and Edwards (1968), 10 persons were affected by test, 3 others were (by genealogic connections) presumably affected and 2 others were reportedly affected. Male-to-male transmission occurred. Richards and Wrong (1972) described familial renal tubular acidosis in a mother and her 3 children. Morris (1970) suggested that at least 3 types of renal tubular acidosis could be recognized: a classic type (RTA I), in which the bicarbonate threshold is normal and the defect is primarily in the distal tubule; a proximal type (RTA II, see 604278), in which the bicarbonate threshold is normal and the defect is primarily in the proximal tubule; and a 'dislocation,' or bicarbonate-wasting, type (RTA III, see 267200). A phenocopy of the genetic disorder is produced by amphotericin B (McCurdy et al., 1968). Buckalew et al. (1974) suggested that there are 2 autosomal dominant forms of RTA, one with hypercalciuria and one without. Hamed et al. (1979) presented studies of a large kindred that appeared to indicate that absorptive hypercalciuria is an autosomal dominant trait with complete penetrance and variable expressivity, that can lead to renal tubular acidosis and nephrocalcinosis. Buckalew et al. (1974) had also shown in 1 family that hypercalciuria preceded RTA. Chaabani et al. (1994) reported a family in which 28 members had primary RTA I. In this large family, as well as in 2 other families with a small number of affected individuals, some of the affected members were asymptomatic. Clinical abnormalities commonly associated with RTA I, such as nephrocalcinosis and growth retardation, appeared only in 3 cases among offspring when both parents were affected. Linkage studies excluded close linkage to ABO, MNS, GM, and RH. Chaabani et al. (1994) suggested that theirs was the first reported large family with primary RTA I. Other families, such as those reported by Buckalew et al. (1974) and Hamed et al. (1979), had RTA I secondary to hereditary hypercalciuria. In 2 unrelated males with primary renal tubular acidosis, Kondo et al. (1978) found an inactive form of carbonic anhydrase B (CA2; 611492) in red cells. Although antigenically and electrophoretically normal, it showed decreased zinc binding. The zinc contained in isolated enzyme was reduced and enzyme activity in hemolysates was restored by addition of zinc chloride. One mother had depressed CA-B, but no increase in specific activity was observed after addition of zinc. The authors estimated that 41 and 62% of CA-B was of mutant type in their 2 cases and apparently favored dominant inheritance. RTA of prominently distal type associated with osteopetrosis (259730) has been found to have a defect in CA2. Bruce et al ... More on the omim web site

The reference OMIM entry for this protein is 185020

Cryohydrocytosis; chc
Stomatocytosis, cold-sensitive

A number sign (#) is used with this entry because of evidence that cryohydrocytosis (CHC) is caused by heterozygous mutation in the SLC4A1 gene (109270) on chromosome 17q21. Heterozygous mutation in SLC4A1 can also cause Southeast Asian ovalocytosis (166900) and spherocytosis-4 (SPH4; 612653).

DESCRIPTION

Cryohydrocytosis is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by Coles et al., 1999). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by Bogdanova et al., 2010). For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.

CLINICAL FEATURES

Miller et al. (1965) described a 19-year-old man who presented with jaundice and splenomegaly at age 13 years and was found to have moderately severe hemolytic anemia. Splenectomy resulted in clinical improvement, but did not completely resolve the hemolytic anemia. Further investigation revealed stomatocytosis characterized by increased autohemolysis and increased osmotic fragility at 5 degrees compared to 37 degrees C. The parents and a sib were unaffected. The man subsequently sired a son with the same disorder (Townes and Miller, 1980). Cold-sensitive hemolysis was prevented by reduced pH or increased ATP. Since correction was not correlated with glucose metabolism or intracellular levels of ATP, a membrane defect was suggested. Alani et al. (1994) reported a British family from Blackburn with a previous diagnosis of spherocytosis (SPH; see 182900) in which the proband, 2 of his sibs, and his son exhibited temperature-sensitive pseudohyperkalemia. The proband, who had already undergone splenectomy, presented at age 40 years with shortness of breath and was found to have multiple pulmonary emboli. Serum samples showed varying levels of hyperkalemia but there were no features of hyperkalemia on electrocardiogram, suggesting pseudohyperkalemia. Further analysis confirmed pseudohyperkalemia, which was related to the time between sampling and cell separation, and inversely related to the temperature at which the specimen was left to stand before cell separation. Temperature-sensitive pseudohyperkalemia was also demonstrated in the proband's 2 sibs with SPH and in 1 affected son, but not in the proband's wife or in another son who did not have SPH. The authors noted that because hereditary spherocytosis is not rare and pseudohyperkalemia had not previously been reported in association with it, the presence of both in this family might have occurred by chance. Coles et al. (1999) restudied the family from Blackburn that had been reported by Alani et al. (1994). The pedigree then included all 3 sibs of the original proband, their father and paternal grandfather, as well as 2 children of 1 of the proband's affected sisters. Blood films of affected family members revealed stomatocytosis; the authors stated that all families known to them with stomatocytosis had at some stage been diagnosed with 'atypical hereditary spherocytosis.' Hematologic analysis showed marked abnormalities of intracellular sodium and potassium levels in fresh cells, intermediate in severity between those seen in overhydrated ... More on the omim web site

The reference OMIM entry for this protein is 611162

Malaria, susceptibility to malaria, resistance to, included
Malaria, severe, susceptibility to, included
Malaria, severe, resistance to, included
Malaria, cerebral, susceptibility to, included
Malaria, cerebral, resistance to, included

A number sign (#) is used with this entry because variation in several different genes influences susceptibility and resistance to malaria, as well as disease progression and severity. These genes include HBB (141900), ICAM1 (147840), CD36 (173510), CR1 (120620), GYPA (111300), GYPB (111740), GYPC (110750), TNF (191160), NOS2A (163730), TIRAP (606252), FCGR2B (604590), and CISH (602441). In addition, a locus associated with Plasmodium falciparum blood infection level has been mapped to chromosome 5q31-q33 (PFBI; 248310), a locus for susceptibility to mild malaria has been mapped to chromosome 6p21.3 (MALS; 609148), a locus associated with malaria fever episodes has been mapped to chromosome 10p15 (PFFE1; 611384), and a locus for susceptibility to placental malarial infection has been mapped to chromosome 6 (FUT9; 606865). Complete protection from Plasmodium vivax infection is associated with the Duffy blood group-negative phenotype (see 110700). Alpha(+)-thalassemia (141800), the X-linked disorder G6PD deficiency (300908), and Southeast Asian ovalocytosis (109270) are associated with resistance to malaria.

DESCRIPTION

Malaria, a major cause of child mortality worldwide, is caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the 4 species that infect humans, P. falciparum causes the most severe forms of malaria and is the major cause of death and disease. Although less fatal, P. malariae, P. ovale, and, in particular, P. vivax infections are major causes of morbidity. The parasite cycle involves a first stage in liver cells and a subsequent stage at erythrocytes, when malaria symptoms occur. A wide spectrum of phenotypes are observed, from asymptomatic infection to mild disease, including fever and mild anemia, to severe disease, including cerebral malaria, profound anemia, and respiratory distress. Genetic factors influence the response to infection, as well as disease progression and severity. Malaria is the strongest known selective pressure in the recent history of the human genome, and it is the evolutionary driving force behind sickle-cell disease (603903), thalassemia (see 141800), glucose-6-phosphatase deficiency (300908), and other erythrocyte defects that together constitute the most common mendelian diseases of humans (Kwiatkowski, 2005; Campino et al., 2006).

PATHOGENESIS

Compared with other microorganisms, P. falciparum malaria parasites reach very high densities in blood. P. falciparum-infected erythrocytes (PfIRBCs) induce ICAM1 (147840) expression on human brain microvascular endothelial cells (HBMECs), but not on human umbilical vein endothelial cells. PfIRBCs compromise the electrical function of brain endothelium independently of PfIRBC binding phenotype, suggesting a role for soluble parasite factors. By performing genomewide transcriptional profiling of HBMECs after exposure to isogenic PfIRBCs, followed by ELISA for protein identification, Tripathi et al. (2009) identified upregulated molecules involved in immune response, apoptosis and antiapoptosis, inflammatory response, cell-cell signaling, and signal transduction and activation of the NF-kappa-B (see 164011) cascade. Proinflammatory molecules, including CCL20 (601960), CXCL1 (155730), CXCL2 (139110), IL6 (147620), and IL8 (146930), were upregulated more than 100-fold. Tripathi et al. (2009) concluded that PfIRBC exposure to HBMECs results in a predominantly proinflammatory response mediated by NF-kappa-B activati ... More on the omim web site

The reference OMIM entry for this protein is 611590

Renal tubular acidosis, distal, with hemolytic anemia
Rta, distal, autosomal recessive, with hemolytic anemia renal tubular acidosis, distal, with normal red cell morphology, included

A number sign (#) is used with this entry because autosomal recessive distal renal tubular acidosis (dRTA) with hemolytic anemia is caused by mutation in the SLC4A1 gene (109270). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive distal RTA, see 267300.

CLINICAL FEATURES

Tanphaichitr et al. (1998) described a Thai brother and sister with autosomal recessive distal RTA and hemolytic anemia. 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.

MOLECULAR GENETICS

Tanphaichitr et al. (1998) described novel SLC4A1 mutations in a Thai family with a recessive syndrome of distal renal tubular acidosis and hemolytic anemia in which red cell anion transport was normal. 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 genetic and functional data suggested that the homozygous SLC4A1 G701D mutation caused 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; see 109270). The SAO deletion mutation (109270.0002) in the SLC4A1 gene occurred in many of the families but did not itself result in dRTA. Compound heterozygotes of each of 3 dRTA mutations (G701D; A858D, 109270.0020; and 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. 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 proband was a 5-year-old boy with dRTA, rickets, failure to thrive, nephrocalcinosis, and hypokalemic/hyperchloremic metabolic acidosis with a urine pH of 7.00. He had a normal hemoglobin level and normal red cell morphology. The proband was found to have compound heterozygous G701D (109270.0016)/S773P (109270.0026) mutations, inherited from his clinically normal mother and father, respectively. In the second family, a 19-year-old man and his 15-year-old sister had dRTA and Southeast Asian ovalocytosis, and were compound heterozygotes for the SAO deletion mutation (109270.0002) and an R602H mutation (109270.0027). Their mother had SAO and an unaffected brother was heterozygous for the R602P mutation. 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.

POPULAT ... More on the omim web site

The reference OMIM entry for this protein is 612653

Spherocytosis, type 4; sph4
Spherocytosis, hereditary, 4; hs4

A number sign (#) is used with this entry because spherocytosis type 4 is caused by mutation in the band 3 gene (SLC4A1, EPB3; 109270). For a general description and a discussion of genetic heterogeneity of spherocytosis, see SPH1 (182900).

CLINICAL FEATURES

Prchal et al. (1991) studied a family with autosomal dominant hereditary spherocytosis associated with deficiency of erythrocyte band 3 protein. Del Giudice et al. (1992) reported a family in which a dominantly inherited form of hereditary spherocytosis was associated with deficiency of band 3, resulting in an increased spectrin/band 3 ratio. Since deficiency of spectrin is a much more frequent cause of hereditary spherocytosis, the usual finding is a decreased spectrin/band 3 ratio. An increased spectrin/band 3 ratio, pointing to a band 3 defect, was found in 2 families with hereditary spherocytosis studied by Lux et al. (1990). Del Giudice et al. (1993) described a family in which both hereditary spherocytosis due to band 3 deficiency and beta-0-thalassemia trait due to codon 39 (C-T) mutation (141900.0312) were segregating. Two subjects with HS alone had a typical clinical form of spherocytosis with anemia, reticulocytosis, and increased red cell osmotic fragility. Two who coinherited HS and beta-thalassemia trait were not anemic and showed a slight, well-compensated hemolysis. Thus, the beta-thalassemic trait partially corrected or 'silenced' HS caused by band 3 deficiency.

PATHOGENESIS

Saad et al. (1991) examined the mechanism underlying band 3 deficiency in a subset of patients with hereditary spherocytosis.

MAPPING

Prchal et al. (1991) performed linkage analysis in a family with autosomal dominant hereditary spherocytosis associated with deficiency of erythrocyte band 3 protein. They excluded linkage with alpha-spectrin (182860), beta-spectrin (182870), and ankyrin (612641), but found a suggestion of linkage to EPB3 (SLC4A1). They used RFLPs not only in the EPB3 gene but also in the NGFR gene (162010) which, like EPB3, maps to 17q21-q22. A maximum lod score of 11.40 at theta = 0.00 was observed. Study of 42 members from 4 generations revealed a consistent linkage of spherocytosis with 1 particular haplotype generated by the 4 probes that were used.

MOLECULAR GENETICS

In a 28-year-old female with congenital spherocytic hemolytic anemia, Jarolim et al. (1991) identified a missense mutation in the SLC4A1 gene (109270.0003). Jarolim et al. (1994) described duplication of 10 nucleotides in the SLC4A1 gene (109270.0005) in a family with 5 individuals affected by spherocytosis in 3 generations. Before splenectomy, the affected subjects had a compensated hemolytic disease with reticulocytosis, hyperbilirubinemia, and increased osmotic fragility. Eber et al. (1996) found that band 3 frameshift and nonsense null mutations occurred in dominant hereditary spherocytosis. In studies of 46 HS families, 12 ankyrin-1 mutations and 5 band 3 mutations were identified. Among 80 hereditary spherocytosis kindreds studied using denaturing electrophoretic separation of solubilized erythrocyte membrane proteins, Dhermy et al. (1997) recognized 3 prominent subsets: HS with isolated spectrin deficiency, HS with combined spectrin and ankyrin deficiency, and HS with band 3 deficiency. These 3 subsets represented more than 80% of the HS kindreds studied. In 8 dominant HS kindreds with band 3 deficiency mutations were sought. In each, linkage analysis confirmed t ... More on the omim web site

Subscribe to this protein entry history

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 1, 2021: Protein entry updated
Automatic update: OMIM entry 166900 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 612653 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 112010 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 112050 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 130600 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 109270 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 166900 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 179800 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 611590 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 185020 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 110500 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 601550 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 601551 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Feb. 16, 2021: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Feb. 16, 2021: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Feb. 16, 2021: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Feb. 16, 2021: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 612653 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 166900 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 179800 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 110500 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 185020 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 611590 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 601550 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 601551 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 612653 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 112010 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 112050 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 130600 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 109270 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 611590 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 612653 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 166900 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 110500 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 179800 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 185020 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 112010 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 112050 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 601551 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 601550 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 130600 was added.

April 25, 2020: Protein entry updated
Automatic update: OMIM entry 109270 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 110500 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 611590 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 601550 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 612653 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 166900 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 179800 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 112010 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 185020 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 112050 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 109270 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 130600 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 601551 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 4, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 601550 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 166900 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 109270 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 179800 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 110500 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 185020 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 112010 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 611590 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 112050 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 130600 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 612653 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

Nov. 16, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Nov. 16, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

May 26, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 109270 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 110500 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 112010 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 112050 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 130600 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 166900 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 179800 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 185020 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 601550 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 601551 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 611590 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 612653 was added.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 109270 was added.

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed