title: Heterogeneity of Human Neutrophil CD177 Expression Results from CD177P1 Pseudogene Conversion.
abstract: Most humans harbor both CD177neg and CD177pos neutrophils but 1-10% of people are CD177null, placing them at risk for formation of anti-neutrophil antibodies that can cause transfusion-related acute lung injury and neonatal alloimmune neutropenia. By deep sequencing the CD177 locus, we catalogued CD177 single nucleotide variants and identified a novel stop codon in CD177null individuals arising from a single base substitution in exon 7. This is not a mutation in CD177 itself, rather the CD177null phenotype arises when exon 7 of CD177 is supplied entirely by the CD177 pseudogene (CD177P1), which appears to have resulted from allelic gene conversion. In CD177 expressing individuals the CD177 locus contains both CD177P1 and CD177 sequences. The proportion of CD177hi neutrophils in the blood is a heritable trait. Abundance of CD177hi neutrophils correlates with homozygosity for CD177 reference allele, while heterozygosity for ectopic CD177P1 gene conversion correlates with increased CD177neg neutrophils, in which both CD177P1 partially incorporated allele and paired intact CD177 allele are transcribed. Human neutrophil heterogeneity for CD177 expression arises by ectopic allelic conversion. Resolution of the genetic basis of CD177null phenotype identifies a method for screening for individuals at risk of CD177 isoimmunisation.
authors.affiliation: Translational Research Unit, Canberra Hospital, Woden, Australian Capital Territory, Australia.|Clinical Trials Unit, Canberra Hospital, Woden, Australian Capital Territory, Australia.
authors.forename: Zuopeng
authors.identifier: 0000-0002-2005-3279
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Australian Phenomics Facility, Australian National University, Australian Capital Territory, Australia.
authors.forename: Rong
authors.initials: R
authors.lastname: Liang
authors.affiliation: Murdoch Children's Research Institute, Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ohnesorg
authors.affiliation: Department of Immunology, The John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
authors.forename: Vicky
authors.initials: V
authors.lastname: Cho
authors.affiliation: Translational Research Unit, Canberra Hospital, Woden, Australian Capital Territory, Australia.
authors.forename: Wesley
authors.identifier: 0000-0003-2117-6753
authors.initials: W
authors.lastname: Lam
authors.affiliation: Clinical Trials Unit, Canberra Hospital, Woden, Australian Capital Territory, Australia.
authors.forename: Walter P
authors.initials: WP
authors.lastname: Abhayaratna
authors.affiliation: Department of Immunology, Canberra Hospital, Woden, Australian Capital Territory, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gatenby
authors.affiliation: Department of Rheumatology, Canberra Hospital, Woden, Australian Capital Territory, Australia.
authors.forename: Chandima
authors.initials: C
authors.lastname: Perera
authors.affiliation: Australian Phenomics Facility, Australian National University, Australian Capital Territory, Australia.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Australian Phenomics Facility, Australian National University, Australian Capital Territory, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Whittle
authors.affiliation: Murdoch Children's Research Institute, Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Department of Immunology, The John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Department of Immunology, The John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Field
authors.affiliation: Department of Immunology, The John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.affiliation: Translational Research Unit, Canberra Hospital, Woden, Australian Capital Territory, Australia.|Department of Immunology, The John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia.|Department of Immunology, Canberra Hospital, Woden, Australian Capital Territory, Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
mesh_terms: D019268:Antibodies, Antineutrophil Cytoplasmic / Q000096:biosynthesis / Q000276:immunology; D001804:Blood Transfusion, Autologous / Q000009:adverse effects; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D006801:Humans; D007519:Isoantigens / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000276:immunology; D009503:Neutropenia / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011544:Pseudogenes / Q000235:genetics* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D054098:Thrombocytopenia, Neonatal Alloimmune
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D011956:Receptors, Cell Surface