title: Molecular defects underlying the Kell null phenotype.
abstract: 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.
authors.affiliation: Lindsley F. Kimball Research Institute of the New York Blood Center, New York, New York 10021, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: D C
authors.initials: DC
authors.lastname: Russo
authors.forename: A P
authors.initials: AP
authors.lastname: Reiner
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: M Y
authors.initials: MY
authors.lastname: Sy
authors.forename: M J
authors.initials: MJ
authors.lastname: Telen
authors.forename: W J
authors.initials: WJ
authors.lastname: Judd
authors.forename: P
authors.initials: P
authors.lastname: Simon
authors.forename: M J
authors.initials: MJ
authors.lastname: Rodrigues
authors.forename: T
authors.initials: T
authors.lastname: Chabert
authors.forename: J
authors.initials: J
authors.lastname: Poole
authors.forename: S
authors.initials: S
authors.lastname: Jovanovic-Srzentic
authors.forename: C
authors.initials: C
authors.lastname: Levene
authors.forename: V
authors.initials: V
authors.lastname: Yahalom
authors.forename: C M
authors.initials: CM
authors.lastname: Redman
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005091:Exons; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007438:Introns; D007626:Kell Blood-Group System / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D007626:Kell Blood-Group System