title: Genetic mechanism of human neutrophil antigen 2 deficiency and expression variations.
abstract: Human neutrophil antigen 2 (HNA-2) deficiency is a common phenotype as 3-5% humans do not express HNA-2. HNA-2 is coded by CD177 gene that associates with human myeloproliferative disorders. HNA-2 deficient individuals are prone to produce HNA-2 alloantibodies that cause a number of disorders including transfusion-related acute lung injury and immune neutropenia. In addition, the percentages of HNA-2 positive neutrophils vary significantly among individuals and HNA-2 expression variations play a role in human diseases such as myelodysplastic syndrome, chronic myelogenous leukemia, and gastric cancer. The underlying genetic mechanism of HNA-2 deficiency and expression variations has remained a mystery. In this study, we identified a novel CD177 nonsense single nucleotide polymorphism (SNP 829A>T) that creates a stop codon within the CD177 coding region. We found that all 829TT homozygous individuals were HNA-2 deficient. In addition, the SNP 829A>T genotypes were significantly associated with the percentage of HNA-2 positive neutrophils. Transfection experiments confirmed that HNA-2 expression was absent on cells expressing the CD177 SNP 829T allele. Our data clearly demonstrate that the CD177 SNP 829A>T is the primary genetic determinant for HNA-2 deficiency and expression variations. The mechanistic delineation of HNA-2 genetics will enable the development of genetic tests for diagnosis and prognosis of HNA-2-related human diseases.
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, United States of America.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Li
authors.affiliation: American Red Cross, North Central Blood Services, National Neutrophil Reference Laboratory, Saint Paul, Minnesota, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Mair
authors.affiliation: American Red Cross, North Central Blood Services, National Neutrophil Reference Laboratory, Saint Paul, Minnesota, United States of America.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Schuller
authors.affiliation: Department of Clinical and Experimental Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, United States of America; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn; D005838:Genotype; D064368:Healthy Volunteers; D006579:Heterozygote; D006801:Humans; D007519:Isoantigens / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D011956:Receptors, Cell Surface