A novel nonsense mutation found in the CD177 gene of Thai individuals with the HNA‐2 null phenotype

Siriphanthong, Kanokpol; Petvises, Sawang; Thanongsaksrikul, Jeeraphong; Intharanut, Kamphon; Nathalang, Oytip

doi:10.1111/tme.12650

Cited by 3 publications

(8 citation statements)

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“…The SNP c.787A > T is a nonsense SNP that terminates the protein translation and causes the HNA‐2 expression defect. Our previous study revealed that c.787T homozygosity is the primary genetic determinant for HNA‐2 deficiency, 16 which was confirmed by independent studies from other groups 17,18,23,24 …”

Section: Discussionmentioning

confidence: 53%

An accurate genetic assay to identify human neutrophil antigen 2 deficiency

Schuller

2022

Transfusion Medicine

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Objective We aimed to develop accurate and user‐friendly genetic assays to identify the inherited neutrophil antigen‐2 (HNA‐2) deficiency in humans. Background HNA‐2 is one of the most important neutrophil antigens implicated in a number of human disorders. HNA‐2 deficiency or HNA‐2 null is a common phenotype observed in 3%–5% Americans. HNA‐2 null individuals are at risk to produce isoantibodies (or alloantibodies) that play important roles in transfusion‐related acute lung injury, immune neutropenia, and bone marrow graft failure. We previously demonstrated that the CD177 coding SNP 787A > T (c.787A > T) is the most important genetic determinant for HNA‐2 deficiency. However, reliable genetic assays are not available for routine clinical laboratory application up to now. Study Design and Methods A novel polymerase chain reaction (PCR) strategy was used to determine genotypes of the CD177 SNP c.787A > T. In the simplified PCR assay, all allele specific primers and internal control primers were included in the same reaction, which ensures reliability of the assay. In addition, a novel high‐throughput nested TaqMan assay was developed to determine genotypes of c.787A > T for large population genetic analysis of HNA‐2 deficiency. Results CD177 SNP c787A > T genotypes of 396 subjects were 100% concordant among the single PCR reaction method, the nested TaqMan assay, and Sanger Sequencing analysis. Out of 396 subjects, all 18 donors with the CD177 STP homozygous genotype were HNA‐2 null. Conclusion The novel PCR‐based genotyping assay is accurate to identify HNA‐2 deficient individuals and is suitable for clinical laboratories. In addition, the innovative high‐throughput nested TaqMan assay will be useful for large‐scale population screens and genetic studies of HNA‐2 deficiency.

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Section: Discussionmentioning

confidence: 53%

An accurate genetic assay to identify human neutrophil antigen 2 deficiency

Schuller

2022

Transfusion Medicine

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“…The polymorphism at position c.1254 has been previously reported as a low-frequency polymorphism in a large Asian study [8] where only one homozygous individual was identified. In this case, CD177 expression was not significantly affected (CD177+ 85%, Fig-…”

Section: Discussionmentioning

confidence: 88%

“…First described in 1971 as NB1 [1], the human neutrophil antigen 2 (HNA-2/CD177) has been implicated in numerous clinical conditions including autoimmune neutropenia (AIN), neonatal alloimmune neutropenia (NAIN), transfusion-related acute lung injury and haematopoietic stem cell graft failure [2][3][4][5][6][7]. Although many polymorphisms have been described in the CD177 gene there is no definitive assignment of null or altered expression [4,[8][9][10][11][12][13][14][15][16], which is reflected in the current nomenclature [17]. CD177 null frequency has been reported >10% in French and Western Japanese populations, 3%-5% European, Brazilian and North American populations [10,18] and less than 0.05% in Thai/Chinese [19,20].…”

Section: Introductionmentioning

confidence: 99%

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Human neutrophil antigen 2 sequence‐based typing: Joining the hunt for the CD177 answer

et al. 2021

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Background and Objectives: Isoantibodies to human neutrophil antigen 2 (CD177) have been associated with several clinical conditions but to date the molecular basis for altered or non-expression has not been determined. Reliance on phenotyping and crossmatch to investigate these neutropenic clinical cases are inconvenient for the patients and demanding of resources within the laboratory. Therefore, a molecular approach has been introduced to address both issues. Materials and Methods:A DNA panel of 100 randomly selected blood donors were collected and supplemented with 18 DNA samples from blood donors previously shown to be CD177 null. All DNA samples were sequence-based typed for all exons and observed polymorphisms recorded. The DNA from two families previously investigated for neonatal alloimmune neutropenia due to CD177 isoantibodies were also analysed. Results:The incidence of CD177 null could be associated with a known exon 7 single-nucleotide polymorphism in 16/21 known CD177 null samples, which is consistent with previously published findings. Two additional mutations that may lead to null expression were also identified, of which one may be novel. In both family investigations, this same mutation could also be observed in the maternal DNA sample. Conclusion:Based on these observations, introduction of CD177 genotyping into routine use would identify null expression in over 75% (16/21) of associated cases.In turn, this could significantly reduce the need for supplementary testing and associated inconvenience to patients while permitting increased efficiency of laboratory testing. An added benefit would potentially elucidate other clinically relevant mutations and associated antigenic targets.

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“…In contrast, HNA-2 is an isoantigen and has differential expression on neutrophils. mRNA splicing defects along with DNA polymorphism CD177 * 787A>T in association with c.1254G>A, c.955delG, c.1291G>A SNPs have been identified in several HNA-2-deficient individuals in different ethnic groups [ 11 , 12 , 13 , 14 ]. HNA-2 expression has been more commonly studied by flow-cytometry using monoclonal antibodies.…”

Section: Introductionmentioning

confidence: 99%

Phenotyping and Genotyping of HNA: Prevalence, Risk of Alloimmunization, and HNA Incompatibilities in Indians

Gogri

Parihar

Kulkarni

et al. 2022

Transfus Med Hemother

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Background: Antibodies to human neutrophil alloantigens (HNA) are involved in the pathophysiology of several clinical conditions including transfusion-related acute lung injury (TRALI), alloimmune and autoimmune neutropenia, and febrile nonhemolytic transfusion reactions leading to neutropenia. The cognate antigens are polymorphic structures expressed on several glycoproteins on the neutrophils, i.e., antigens HNA-1a, -1b, -1c, and -1d on Fc-γ-receptor IIIb; HNA-2 on CD177; HNA-3a and -3b on choline transporter-like protein 2; HNA-4a and -4b on CD11b/αM subunit of the αMβ2-integrin (CD11b/CD18, Mac-1, CR3); and HNA-5a and -5b on αL-subunit (CD11a) of the αLβ2 integrin (CD11a/CD18), leukocyte function associated molecule (LFA)-1. Currently, there is a lacuna of diagnostic methods for detection of HNA in India. This study aimed to determine the HNA frequencies in Indians, estimate the risk of alloimmunization, and prepare typed neutrophil panels, which can be used to detect HNA antibodies in neutropenia cases. Material and Methods: EDTA blood samples were collected from random 1,054 blood donors. HNA-2 was phenotyped on fresh EDTA samples using FITC labelled monoclonal anti-CD177 by flowcytometry. HNA-1 (FCGR3B) genotyping was carried out by DNA sequencing and PCR-RFLP. Antigens of HNA-3 (SLC44A2) and HNA-5 (ITGAL) were genotyped by PCR-RFLP using TaqαI and Bsp1286I restriction enzymes, respectively, while HNA-4 (ITGAM) was genotyped by PCR-SSP. Results: Allele frequencies of FCGR3B*01, FCGR3B*02, and FCGR3B*03 were found to be 0.433, 0.444, and 0.087, respectively. FCGR3B*01+*02+*03− was the most common genotype (33.78%). Ten individuals showed deficiency of FCGR3B individuals, while 23 showed hyperexpression, i.e., FCGR3B*01+*02+*03+. FCGR3B*04and *05 occurred with a frequency of 0.002 and 0.024. HNA-2 was found to be a high frequency antigen occurring in 98.8% population. Four percent individuals showed atypical expression of CD177 on their neutrophils. Allele frequencies of SLC44A2*01 and SLC44A2*02were 0.812 and 0.188, respectively, and that of ITGAM*01, ITGAM*02, ITGAL*01, and ITGAL*02 were 0.9546, 0.0454, 0.2372, and 0.7628, respectively. Conclusion: This is the first study in India to report the frequencies of HNA among blood donors. Typed neutrophil panels identified in the present study will enable us to investigate suspected cases of immune neutropenia in future.

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A novel nonsense mutation found in the CD177 gene of Thai individuals with the HNA‐2 null phenotype

Cited by 3 publications

References 14 publications

An accurate genetic assay to identify human neutrophil antigen 2 deficiency

An accurate genetic assay to identify human neutrophil antigen 2 deficiency

Human neutrophil antigen 2 sequence‐based typing: Joining the hunt for the CD177 answer

Phenotyping and Genotyping of HNA: Prevalence, Risk of Alloimmunization, and HNA Incompatibilities in Indians

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