Molecular and computational analysis of 45 samples with a serologic weak D phenotype detected among 132,479 blood donors in northeast China

Zhang, Xu; Li, Guiji; Zhang, Zhou; Shao, Chao‐Peng; Huang, Xuying; Li, Lichun; Li, Xiaofeng; Liu, Ying; Fan, Hua; Li, Jianping

doi:10.1186/s12967-019-02134-9

Cited by 16 publications

(23 citation statements)

References 52 publications

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“…RHD*DVI.3 and RHD*weak partial 15 were the most prevalent RhD variant alleles in Zhejiang province. This result was consistent with the distribution of RhD variant alleles in other regions of China ( 9 , 16 , 31 ), but it is completely different from a Caucasian population with a prevalence of less than 5% ( 32 , 35 ). There was no significant similarity or clustering in a particular site between the other rare RhD variant alleles identified in our study and those reported previously ( 3 , 9 ).…”

Section: Discussionsupporting

confidence: 88%

“…This result was consistent with the distribution of RhD variant alleles in To qualify as deleterious, the mutation had to be predicted as damaging by at least two of the three bioinformatics programs used. other regions of China (9,16,31), but it is completely different from a Caucasian population with a prevalence of less than 5% (32,35). There was no significant similarity or clustering in a particular site between the other rare RhD variant alleles identified in our study and those reported previously (3,9).…”

Section: Discussioncontrasting

confidence: 53%

“…Most RhD variants could be traced back to DNA variation, including single nucleotide variation (SNV), multiple nucleotide variants (MNV), base insertions or deletions, and hybrid allele (7)(8)(9). So far, over 400 RHD alleles have been registered and nominated by the International Society of Blood Transfusion (ISBT), which were divided into four categories (https://www.…”

Section: Introductionmentioning

confidence: 99%

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The Significance of RHD Genotyping and Characteristic Analysis in Chinese RhD Variant Individuals

et al. 2021

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BackgroundRhD is the most important and complex blood group system because of its highly polymorphic and immunogenic nature. RhD variants can induce immune response by allogeneic transfusion, organ transplantation, and fetal immunity. The transfusion strategies are different for RhD variants formed by various alleles. Therefore, extensive investigation of the molecular mechanism underlying RhD variants is critical for preventing immune-related blood transfusion reactions and fetal immunity.MethodsRhD variants were collected from donors and patients in Zhejiang Province, China. The phenotypes were classified using the serologic method. The full coding regions of RHD gene were analyzed using the PCR-SBT method. The multiplex ligation-dependent probe amplification (MLPA) assay was used to analyze the genotype and gene copy number. SWISS-MODLE and PyMOL software were used to analyze 3D structures of RhD caused by the variant alleles. The effect of non-synonymous substitutions was predicted using Polymorphism Phenotyping algorithm (PolyPhen-2), Sorting Intolerant From Tolerant (SIFT), and Protein Variation Effect Analyzer (PROVEAN) software.ResultsIn the collected RhD variants, 28 distinct RHD variant alleles were identified, including three novel variant alleles. RH-MLPA assay is advantageous for determining the copy number of RHD gene. 3D homology modeling predicted that protein conformation was disrupted and may explain RhD epitope differential expression. A total of 14 non-synonymous mutations were determined to be detrimental to the protein structure.DiscussionWe revealed the diversity of RHD alleles present in eastern Chinese RhD variants. The bioinformatics of these variant alleles extended our knowledge of RhD variants, which was crucial for evaluating their impact to guide transfusion support and avoid immune-related blood transfusion reactions.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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The Significance of RHD Genotyping and Characteristic Analysis in Chinese RhD Variant Individuals

et al. 2021

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“…9 Several 3D bioinformatic models were proposed before the crystal structure of RhCG was resolved [17][18][19][20][21] and were based essentially on automated modeling tools. [22][23][24][25][26] These studies and others 4,27 have proposed the extracellular positions of RhD residues based almost exclusively on the prediction of the secondary structure (α helices) from the amino acid sequence, without considering the 3D conformation of the protein.…”

Section: Introductionmentioning

confidence: 99%

Insights intoanti‐Dformation in carriers ofRhDvariants through studies of3Dintraprotein interactions

et al. 2021

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Background Many RhD variants associated with anti‐D formation (partial D) in carriers exposed to the conventional D antigen carry mutations affecting extracellular loop residues. Surprisingly, some carry mutations affecting transmembrane or intracellular domains, positions not thought likely to have a major impact on D epitopes. Study Design and Methods A wild‐type Rh trimer (RhD1RhAG2) was modeled by comparative modeling with the human RhCG structure. Taking trimer conformation, residue accessibility, and position relative to the lipid bilayer into account, we redefine the domains of the RhD protein. We generated models for RhD variants carrying one or two amino acid substitutions associated with anti‐D formation in published articles (25 variants) or abstracts (12 variants) and for RHD*weak D type 38. We determined the extracellular substitutions and compared the interactions of the variants with those of the standard RhD. Results The findings of the three‐dimensional (3D) analysis were correlated with anti‐D formation for 76% of RhD variants: 15 substitutions associated with anti‐D formation concerned extracellular residues, and structural differences in intraprotein interactions relative to standard RhD were observed in the others. We discuss the mechanisms by which D epitopes may be modified in variants in which the extracellular residues are identical to those of standard RhD and provide arguments for the benignity of p.T379M (RHD*DAU0) and p.G278D (RHD*weak D type 38) in transfusion medicine. Conclusion The study of RhD intraprotein interactions and the precise redefinition of residue accessibility provide insight into the mechanisms through which RhD point mutations may lead to anti‐D formation in carriers.

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“…RHD*weak D type 15, RHD* DEL1, and RHD*DVI.3 are the most prevalent in the Chinese population, while other 61 RHD variants have been reported. [1][2][3] This report describes the proband and his daughter in a Chinese family with a novel allele RHD c.1228-1G>C.…”

mentioning

confidence: 99%

A new RHD variant allele caused by an RHDc.1228‐1G>C mutation in a Chinese family

Liang

Zhuang

et al. 2021

Transfusion

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Molecular and computational analysis of 45 samples with a serologic weak D phenotype detected among 132,479 blood donors in northeast China

Cited by 16 publications

References 52 publications

The Significance of RHD Genotyping and Characteristic Analysis in Chinese RhD Variant Individuals

The Significance of RHD Genotyping and Characteristic Analysis in Chinese RhD Variant Individuals

Insights intoanti‐Dformation in carriers ofRhDvariants through studies of3Dintraprotein interactions

A new RHD variant allele caused by an RHDc.1228‐1G>C mutation in a Chinese family

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