Blood Group Antigen Gene Mutation Database

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Kell Blood Group System

Introduction

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 34 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 was included as part of the Kell blood group system but now is considered an independent 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).

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.

Disease association

None well documented for alleles of Kell glycoproten; however, the absence of XK protein (McLeod phenotype) is associated with red cell acanthocytosis and late onset forms of muscular dystrophy and cardiomyopathy characterized by elevated levels of serum creatine phosphokinase. Also, neurological defects are common, presenting initially as areflexia and sometimes progressing to choreiform movements. However, in some individuals , despite mutations in XK protein, neurological and clinical findings are minimal (Jung et al. Transfusion 43, 928,2003; Walker et al. Transfusion 47, 299, 2007)

Historical aspects

Antibody to KEL1 glycorprotein was first described in 1945 and was found in maternal serum that caused anemia in a newborn infant (Coombs et al., Br. J. Pathol. 26:255, 1945). Subsequent serological studies revealed the polymorphic complexity of the Kell blood group system (for reviews see: Marsh et al., Transfusion Med. Rev. 1:4, 1987 and Reid and Lomas-Francis in "Blood Group Antigen Facts Book," p175-208, Academic Press, 1997). The importance of the association of Kell and XK was deduced from studies on the Ko-null (Marsh et al., Br. J. Haematol., 29: 247, 1975) and McLeod phenotypes and recognition of the clinical symptoms that accompany the McLeod phenotype (Allen et al., Vox Sang. 6:555, 1961; Wimer et al., Br. J. Haematol., 36:219, 1977). 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 (Redman et al. and Redman et al., Br. J. Haematol., 68:131, 1988). 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 (Khamlichi et al., Eur. J. Biochem. 228: 931, 1995) 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 (Lee et al., Blood, 94:1, 1999). The endothelins are potent vasoconstrictors that also act as mitogens and are involved in developmental processes by affecting migration of neural crest derived cells.

About the alleles

As determined by serological analyses, at least 34 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. A relatively large number of null alleles has been observed, many occuring through mutations resulting in termination codons.( In the list of alleles, "KEL mod" designates alleles that are weakly expressed). 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.).

In the list of alleles, KEL sequence M64934 is used as reference ( atg, at nt 121 is used as the initiation site; 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.)The reference allele used in the database is allele K2 that shows a "C" at nt 578 or a "T" at res 193; the antithetical allele K1 shows a "T" at nt 578 and a "M" at res.193.

KEL1 and KEL2 cDNAs were used recently to generate transgenic mice expressing either Kel1 or Kel2 antigen; this repesents an important murine system to study red cell immunology (Smith NH et al. Transfusion 2012 52 2620-2630).

Other database IDs and links

Literature

New PubMed entries with the terms Kell and blood from the last 30 days.
NCBI Book Sections with the terms Kell and blood.

Contributors

Colvin Redman, Ph.D., and Soohee Lee, Ph.D., Lindsley F. Kimball Research Institute The New York Blood Center, 310 East 67th St., New York, N.Y. 10021; Tel: 212-570-3059; Fax: 212-879-3059

Contributors for specific alleles are listed with the alleles.

Links