{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The Kell (KEL) glycoprotein is a type II transmembrane metalloprotease that plays a dual role in human physiology. Biochemically, Kell functions as an endothelin‐3–converting enzyme, processing its substrate “big endothelin‐3” into the vasoactive peptide endothelin‐3. Structural studies reveal that Kell comprises two globular domains, with the enzyme’s active site located in its membrane‐proximal domain; although it shares catalytic motifs with other M13 family metalloproteases (such as neutral endopeptidase), distinct substrate–binding characteristics impart unique functional properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n On red blood cells (RBCs), Kell is expressed as a component of a disulfide‐linked complex with the XK (or Kx) protein. This association is critical for the proper presentation of Kell antigens and for maintaining RBC membrane integrity and ion homeostasis. Disruption of the Kell/XK complex can alter ion transport properties and is implicated in conditions such as McLeod syndrome, a neuroacanthocytosis characterized by abnormal RBC morphology and neuromuscular deficits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic diversity at the KEL locus results in over 20 antigens within the Kell blood group system; such polymorphisms render Kell one of the most immunogenic systems after ABO and Rh. As a consequence, antibodies directed against Kell antigens are a common cause of hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. High‐throughput genotyping and molecular analyses have identified novel silenced and variant KEL alleles that not only influence the antigenic profile but may also modulate the enzyme’s activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": " Furthermore, detailed molecular studies have characterized allelic variants that exhibit differences in Kell expression levels and endothelin‐3–converting activity, underscoring the clinical relevance of KEL genotyping in transfusion medicine."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, evolutionary analyses have identified a signature of positive selection in genomic regions encompassing KEL, suggesting that selective pressures—possibly related to host immunity or vascular regulation—have shaped its variability in human populations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Together, these diverse studies establish Kell as a multifunctional protein that not only executes critical enzymatic processing of peptide substrates but also defines an immunologically significant determinant on RBCs, thereby influencing both vascular homeostasis and transfusion outcomes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Audrey Clapéron, Christiane Rose, Pierre Gane, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Kell protein of the common K2 phenotype is a catalytically active metalloprotease, whereas the rare Kell K1 antigen is inactive. Identification of novel substrates for the Kell protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M500100200"}], "href": "https://doi.org/10.1074/jbc.M500100200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15769748"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15769748"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Soohee Lee, Asim K Debnath, Colvin M Redman "}, {"type": "b", "children": [{"type": "t", "text": "Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-05-1564"}], "href": "https://doi.org/10.1182/blood-2003-05-1564"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12842980"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12842980"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Quan Sha, Colvin M Redman, Soohee Lee "}, {"type": "b", "children": [{"type": "t", "text": "Endothelin-3-converting enzyme activity of the KEL1 and KEL6 phenotypes of the Kell blood group system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M507776200"}], "href": "https://doi.org/10.1074/jbc.M507776200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16423827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16423827"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Audrey Clapéron, Claude Hattab, Vincent Armand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Kell and XK proteins of the Kell blood group are not co-expressed in the central nervous system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.brainres.2007.01.106"}], "href": "https://doi.org/10.1016/j.brainres.2007.01.106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17379193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17379193"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Alicia Rivera, Siok Yuen Kam, Mengfatt Ho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood Cells Mol Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bcmd.2012.10.002"}], "href": "https://doi.org/10.1016/j.bcmd.2012.10.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23122227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23122227"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiang Zhu, Alicia Rivera, Mari S Golub, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hematol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajh.21453"}], "href": "https://doi.org/10.1002/ajh.21453"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19544475"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19544475"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Stefan Meyer, Caren Vollmert, Nadine Trost, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-throughput Kell, Kidd, and Duffy matrix-assisted laser desorption/ionization, time-of-flight mass spectrometry-based blood group genotyping of 4000 donors shows close to full concordance with serotyping and detects new alleles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transfusion (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/trf.12715"}], "href": "https://doi.org/10.1111/trf.12715"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24845979"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24845979"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Amanda Mener, Connie M Arthur, Seema R Patel, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "B cells require Type 1 interferon to produce alloantibodies to transfused KEL-expressing red blood cells in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transfusion (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/trf.14288"}], "href": "https://doi.org/10.1111/trf.14288"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28836263"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28836263"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gregory A Denomme "}, {"type": "b", "children": [{"type": "t", "text": "Kell and Kx blood group systems."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunohematology (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26308465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26308465"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yanli Ji, Barbera Veldhuisen, Peter Ligthart, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel alleles at the Kell blood group locus that lead to Kell variant phenotype in the Dutch population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transfusion (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/trf.12838"}], "href": "https://doi.org/10.1111/trf.12838"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25156717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25156717"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Carla L Dinardo, Theo G M Oliveira, Shannon Kelly, et al. 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