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J. Biol. Chem., Vol. 276, Issue 29, 27281-27289, July 20, 2001

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Molecular Defects Underlying the Kell Null Phenotype^*

From the ^a Lindsley F. Kimball Research Institute of the New York Blood Center, New York, New York 10021, ^c University of Washington, Seattle, Washington 98195, ^d Duke University Medical Center, Durham, North Carolina 27710, ^e University of Michigan Medical Center, Ann Arbor, Michigan 48109, ^f EFS Saint Pierre 97448, Reunion Island, ^g Lisbon Blood Regional Center, Lisbon 1700, Portugal, ^h International Blood Group Reference Laboratory, Bristol B510 5ND, United Kingdom, ⁱ National Blood Transfusion Institute, Belgrade 11000, Yugoslavia, and ^j Blood Services Center, Magen David Adom, Ramat Gan, Israel

Expression of the Kell blood group system is dependent on two proteins, Kell and XK, that are linked by a single disulfide bond. Kell, a type II membrane glycoprotein, is a zinc endopeptidase, while XK, which has 10 transmembrane domains, is a putative membrane transporter. A rare phenotype termed Kell null (Ko) is characterized by the absence of Kell protein and Kell antigens from the red cell membrane and diminished amounts of XK protein. We determined the molecular basis of eight unrelated persons with Ko phenotypes by sequencing the coding and the intron-exon splice regions of KEL and, in some cases, analysis of mRNA transcripts and expression of mutants on the cell surface of transfected cells. Six subjects were homozygous: four with premature stop codons, one with a 5' splice site mutation, G to A, in intron 3, and one with an amino acid substitution (S676N) in exon 18. Two Ko persons with premature stop codons had identical mutations in exon 4 (R128Stop), another had a different mutation in exon 4 (C83Stop), and the fourth had a stop codon in exon 9 (Q348Stop). Two Ko persons were heterozygous for two mutations. One had a 5' splice site mutation (G to A) in intron 3 of one allele that caused aberrant splicing and exon skipping, and the other allele had an amino acid substitution in exon 10 (S363N). The other heterozygote had the same amino acid substitution in exon 10 (S363N) in one allele and a premature stop codon in exon 6 (R192Stop) in the other allele. The S363N and S676N mutants, expressed in 293T cells, were retained in a pre-Golgi compartment and were not transported to the cell surface, indicating that these mutations inhibit trafficking. We conclude that several different molecular defects cause the Kell null phenotype.

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