title: Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression.
abstract: Members of the human KIR (killer cell immunoglobulin-like receptor) class I major histocompatibility complex receptor gene family contain multiple promoters that determine the variegated expression of KIR on natural killer cells. In order to identify novel genetic alterations associated with decreased KIR expression, a group of donors was characterized for KIR gene content, transcripts and protein expression. An individual with a single copy of the KIR2DL1 gene but a very low level of gene expression was identified. The low expression phenotype was associated with a single-nucleotide polymorphism (SNP) that created a binding site for the inhibitory ZEB1 (Zinc finger E-box-binding homeobox 1) transcription factor adjacent to a c-Myc binding site previously implicated in distal promoter activity. Individuals possessing this SNP had a substantial decrease in distal KIR2DL1 transcripts initiating from a novel intermediate promoter located 230 bp upstream of the proximal promoter start site. Surprisingly, there was no decrease in transcription from the KIR2DL1 proximal promoter. Reduced intermediate promoter activity revealed the existence of alternatively spliced KIR2DL1 transcripts containing premature termination codons that initiated from the proximal KIR2DL1 promoter. Altogether, these results indicate that distal transcripts are necessary for KIR2DL1 protein expression and are required for proper processing of sense transcripts from the bidirectional proximal promoter.
authors.affiliation: Basic Science Program, Leidos Biomedical Research Inc., Lab of Experimental Immunology, Frederick National Lab, Frederick, MD, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Wright
authors.affiliation: Basic Science Program, Leidos Biomedical Research Inc., Lab of Experimental Immunology, Frederick National Lab, Frederick, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Huehn
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: O'Connor
authors.affiliation: Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cooley
authors.affiliation: Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: 1] Basic Science Program, Leidos Biomedical Research Inc., Lab of Experimental Immunology, Frederick National Lab, Frederick, MD, USA [2] Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Anderson
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054342:Receptors, KIR2DL1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C093100:KIR2DL1 protein, human; D012333:RNA, Messenger; D054342:Receptors, KIR2DL1; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1