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Polymorphism

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Description

The Kell blood group (also known as the Kell antigen system or Kell-Cellano system) is determined by a group of antigens on the human red blood cell surface. Kell antigens are targets for autoimmune or alloimmune diseases which destroy red blood cells. The Kell antigens are peptides found within the kell protein, a 93 kilodalton transmembrane zinc-dependent endopeptidase which is responsible for cleaving endothelin-3. (1) (2)

There are several alleles of the gene which creates Kell protein. Two such alleles, K1 (Kell) and K2 (Cellano), are the most common. The kell protein is tightly bound to a second protein, XK, by a disulfide bond. Absence of the XK protein (such as through gene deletion), leads to marked reduction of the Kell antigens on the red blood cell surface. Absence of the Kell protein (K0), however, does not affect the XK protein. (3)

Historical aspects

The first Kell system antibody was described in 1946, shortly after the implementation of the use of the then recently described rabbit anti-human globulin reagent. The system's clinical importance was obvious from the first case: an example of hemolytic disease of the newborn. A pregnant woman named Mrs. Kellacher was the first patient described with antibodies to K1, and the Kell group was named after her. (4) Mrs. Cellano was likewise a pregnant woman with the first described antibodies to K2. The K0 phenotype was first described in 1957 and the McLeod phenotype was found in Hugh McLeod, a Harvard dental student, in 1961. (5),(6) (7). Subsequent serological studies revealed the polymorphic complexity of the Kell blood group system (for reviews see 8 and 9).

The importance of the association of Kell and XK was deduced from studies on the Ko-null (10) and McLeod phenotypes and recognition of the clinical symptoms that accompany the McLeod phenotype (11, 12). Isolation of Kell and XK proteins from red blood cells, with specific alloimmune antibodies, demonstrated that Kell antigens are carried on a 93 kDa protein and Kx on a protein that migrates on SDS-PAGE as a 37 kDa polypetide (13). Molecular cloning followed, establishing Kell as a type II glycoprotein homologous with zinc endopeptidases (Lee et al.) and XK as a unique protein that spans the membrane ten times (Ho et al.). The many polymorphic forms of Kell, which express different antigens, were shown to be due to single base changes that encode different amino acids (Lee S). The disulfide linkage of Kell and XK was demonstrated (14) as occurring between Kell Cys 72 and XK Cys347 (Russo et al.). The Kell component of Kel/XK complex was shown to be an enzyme that preferentially cleaves big endothelin-3, an inactive intermediate precursor, at Trp22-Ile22, producing endothelin-3, a potent 21 amino acid peptide (15). The endothelins are potent vasoconstrictors that also act as mitogens and are involved in developmental processes by affecting migration of neural crest derived cells.

As with most systems, over the years, more antigens have been found that were proven by inheritance to be of the Kell blood group system. At present it is a system comprised of 22 blood group antigens, several having been shown to be products of allelic genes. Some of the antigens have also shown a distinct racial prevalence (K antigen is more frequently found in Northern European, the Jsa antigen is most frequently found in those of African descent and the Kpc antigen has been more frequently found in Japanese). All of this was very suggestive of a chromosome location that might have three or more regions with mutation points.

Discussion

The Kell system of blood groups may be looked upon as a pale shadow of the Rh system. It similarly is determined by three closely linked loci, each of which can be occupied by one of a pair of allelic genes, K and k, Kpa and Kpb, and Jsa and Jsb. The K gene, like D in the Rh system, gives rise to an antigen to which mothers not infrequently become immunized, so that their infants suffer from haemolytic disease of the newborn. The K gene and its antigenic product are almost entirely confined to the white or caucasoid peoples, and Jsa to the negroid or African ones. (16)

Genomics

The expression of the Kell genes is modified by epistatic effects, both from the Kell locus and from at least two regulatory genes, one of which is X-borne (17)

The Kell antigens are encoded by a chromosomal location on the long arm of chromosome 7. They are located on a 93 kDa type II glycoprotein that makes a single pass through the membrane, is glycosylated at five sites and functions as a metalloprotease. The Kell antigen appears to be found on erythroid and nonerythroid tissue (primarily in testis).

This system, as with several other systems, has examples of "depressed phenotypes" and "null phenotypes". The McLeod phenotype, or McLeod syndrome (first detected during the investigation of the cells of a Dr. McLeod) have suppression of all inherited Kell blood group antigens, in addition to a unique red blood cell morphology; acanthocytes. The Kell antigens in McLeod syndrome are poorly detected by laboratory tests. Interestingly, the "null phenotype" cells, referred to as K0, which by definition have no Kell blood group antigens, has normal discocytes.

The McLeod gene encodes the XK protein, a protein with structural characteristics of a membrane transport protein, and appears to be required for proper synthesis or presentation of the Kell antigens on the red blood cell surface. In nonerythroid tissues, as exemplified by skeletal muscle, Kell is disulfide-linked to XK.

Alleles

Antigens are carried on a 93 kDa type II glycoprotein that is the product of a single gene, KEL, spanning 19 exons. Kell glycoprotein is linked by a single disulfide bond to a 444 amino acid integral membrane protein, XK, that traverses the membrane 10 times. XK is the product of a single gene, XK, that is organized in three exons. Kell and XK are associated phenotypically. At least 23 antigens are associated with the Kell glycoprotein and XK expresses a single antigen. Because Kell and XK are covalently linked and are linked phenotypically, XK is included as part of the Kell blood group system.

Function of proteins

Kell glycoprotein is a member of the Neprilysin (M13) sub-family of zinc endopeptidases whose principal function is the activation of bioactive peptides by specific proteolytic cleavage of inactive precursor polypeptides. It preferentially cleaves big endothelin-3, a 41 amino acid polypeptide, at Trp21-Ile22, creating bioactive endothelin-3. A crystal model of the Kell protein based on the crystal structure of the ectodomain of neutral endopeptidase indicates that Kell and NEP use the same homologous amino acids in coordination of zinc and in peptide hydrolysis, but different amino acids in substrate binding (Lee et al., Blood, 2003, 102:3028).The function of XK is not yet known but its sequence analysis predicts a membrane transport protein. Its absence is associated with pathological conditions (see below).

Tissue distribution

Kell glycoprotein is expressed primarily in eythroid tissues and in testis; expression is less in a number of other tissues, including various parts of the brain, lymphoid organs, heart and skeletal muscle. XK is primarily expressed in erythroid tissues and skeletal muscle with lower levels of expression in pancreas, heart, brain, and several other tissues.

Disease association

Kell antigens are important in transfusion medicine, autoimmune hemolytic anemia, and hemolytic disease of the newborn. Individuals who lack a specific Kell antigen may develop antibodies against Kell antigens when transfused with blood containing that antigen. Subsequent blood transfusions may be marked by destruction of the new cells by these antibodies, a process known as hemolysis. People without Kell antibodies (K0), must be transfused with blood from donors who are also K0 to prevent hemolysis.

Autoimmune hemolytic anemia (AIHA) occurs when the body produces an antibody against a blood group antigen on its own red blood cells. The antibodies lead to destruction of the red blood cells with resulting anemia. Similarly, a pregnant woman may develop antibodies against fetal red blood cells, resulting in destruction, anemia, and hydrops fetalis in a process known as hemolytic disease of the newborn (HDN). Both AIHA and HDN may be severe when caused by anti-Kell antibodies. (18)

McLeod phenotype

In males the absence of XK protein (McLeod phenotype) causes variable red cell acanthocytosis due to a defect in the inner leaflet bilayer, as well as mild hemolysis. McLeod females have only occasional acanthocytes and very mild hemolysis; the lesser severity is thought to be due to X chromosome inactivation via the Lyon effect.

Some individuals with McLeod phenotype develop neuropathy or psychiatric symptoms, producing a syndrome presenting initially as areflexia and sometimes progressing to a syndrome that mimics chorea. (19)

The gene for McLeod syndrome is physically close on the X chromosome to the gene for chronic granulomatous disease and individuals with one disease may have both as a result of genetic linkage. (20). late onset forms of muscular dystrophy and cardiomyopathy characterized by elevated levels of serum creatine phosphokinase.

Other associations

Evidence supports a genetic link between the Kell blood group (on chromosome 7 q33) and the ability to taste phenylthiocarbamide, or PTC, a bitter-tasting thiourea compound. (21) (22) Bitter taste receptor proteins in the taste buds of the tongue that recognise PTC are encoded on nearby chromosome locus 7 q35-6.

About the alleles

KEL: As determined by serological analyses, at least 23 unique antigens are associated with the Kell glycoprotein; in five instances anthitetical antigens have been found ,the rest being indepedently expressed antigens.(The antigens are designated numerically, a minus sign indicating their absence; most probably those lacking the minus sign are expressed on the "wild type" protein). Thus, the common Kell serologic phenotype reads as follows: -1, 2, -3, -21, 4, 5, -6, 7, 11, -17, 14, -24, -10, -12, 13, 16, -18, -19, 20, -22, -23, -25, -26, Kx. The known antithetical partners are K2/K1, K4/K3/K21, K7/K6, K11/K17, K14/K24; the antithetical partners of the other antigens are unknown so far. It appears that the Kell glycoprotein, encoded by the "wild type" KEL gene, carries a number of epitopes, that can be distinguished serologically; therefore, the polymorphism in this system arises from expression, on the background of the KEL gene, of a mosaic of mutations at the sites of one or more epitopes. So far, the documented mutations all occurred at sites of a number of single epitopes; all result from single nucleotide changes in the KEL gene. Their incidence varies from 20% in some populations, to single families. The crystal model of Kell protein indicates that the polymorphic residues reside on the outer rim of the protein, away from the catalytic site (Lee et al.). XK: The product of the XK gene is associated both structurally and phenotypically with the Kell system. In particular, the absence of the Kx antigen and weakened activity of all Kell antigens are characteristic of the McLeod syndrome (occurrence observed in less than 100 families). Alleles of XK shown in the list of alleles have been documented in individuals with McLeod syndrome or/and depressed reactivity of Kell antigens. In addition, in several McLeod patients the XK locus was excluded form its chromosomal locus; these alterations do not result in true alleles.

In the list of alleles, KEL: sequence M64934 is used as reference (atg is at nt 121); a second possible initiation site occurs at nt.178, Met; the isolated Kell protein has a blocked N terminus and the correct initiation site has not been experimentally determined. XK: Sequence Z32684 taken as reference (atg is at nt. 83).

Links

Attribution

References


1. Lee S, Wu X, Reid M, Zelinski T, Redman C. Molecular basis of the Kell (K1) phenotype. Blood. 1995 Feb 15;85(4):912-6. PMID 7849312

2. Lee S, Lin M, Mele A, Cao Y, Farmar J, Russo D, Redman C. Proteolytic processing of big endothelin-3 by the kell blood group protein. Blood. 1999 Aug 15;94(4):1440-50. PMID 10438732

3. Yu LC, Twu YC, Chang CY, Lin M. Molecular basis of the Kell-null phenotype: a mutation at the splice site of human KEL gene abolishes the expression of Kell blood group antigens. J Biol Chem. 2001 Mar 30;276(13):10247-52. Epub 2000 Dec 27. PMID 11134029

4. Coombs RRA, Mourant AE, Race RR. A new test for the detection of weak and incomplete Rh agglutinins. Br J Exp Pathol 1945;26:255

5. Chown B, Lewis M, Kaita K. A new Kell blood-group phenotype. Nature. 1957 Oct 5;180(4588):711. PMID 13860532

6. Allen FH Jr, Krabbe SM, Corcoran PA. A new phenotype (McLeod) in the Kell blood-group system. Vox Sang. 1961 Sep;6:555-60. PMID 13477267

7. Coombs et al., Br. J. Pathol. 26:255, 1945

8. Marsh et al., Transfusion Med. Rev. 1:4, 1987

9. Reid and Lomas-Francis in "Blood Group Antigen Facts Book," p175-208, Academic Press, 1997

10. Marsh et al., Br. J. Haematol., 29: 247, 1975

11. Allen et al., Vox Sang. 6:555, 1961

12. Wimer et al., Br. J. Haematol., 36:219, 1977

13. Redman et al. and Redman et al., Br. J. Haematol., 68:131, 1988

14. Khamlichi et al., Eur. J. Biochem. 228: 931, 1995

15. Lee et al., Blood, 94:1, 1999

16. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983.

17. SCARF exchange

18. Wiener CP, and Widness JA. Decreased fetal erythropoiesis and hemolysis in Kell hemolytic anemia. American Journal of Obstetrics and Gynecology. 1996 174: 547-55 PMID 8623782

19. Danek A, Rubio JP, Rampoldi L, Ho M, Dobson-Stone C, Tison F, Symmans WA, Oechsner M, Kalckreuth W, Watt JM, Corbett AJ, Hamdalla HH, Marshall AG, Sutton I, Dotti MT, Malandrini A, Walker RH, Daniels G, Monaco AP. McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol. 2001 Dec;50(6):755-64. PMID 11761473

20. Marsh WL, Oyen R, Nichols ME, Allen FH Jr. Chronic granulomatous disease and the Kell blood groups. Br J Haematol. 1975 Feb;29(2):247-62. PMID 1191546

21. Crandall BF, Spence MA. Linkage relations of the phenylthiocarbamide locus (PTC). Hum Hered. 1974;24(3):247-52.PMID 4435792

22. Conneally PM, Dumont-Driscoll M, Huntzinger RS, Nance WE, Jackson CE. Linkage relations of the loci for Kell and phenylthiocarbamide taste sensitivity. Hum Hered. 1976;26(4):267-71. PMID 976995

23. Blumenfeld OO, Patnaik SK. Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Human Mutation. 2004 Jan; 23(1):8-16. PubMed ID: 14695527

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