Novel RHD allele with c.333C>G change predicted to encode p.Phe111Leu.
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ABSTRACT:
SUBMITTER: Alluin G
PROVIDER: S-EPMC9804188 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
Novel RHD allele with c.333C>G change predicted to encode p.Phe111Leu.
Alluin Gauthier G Durieux-Roussel Elisabeth E Fayoux Pierre P Pirenne France F Tournamille Christophe C Floch Aline A
Transfusion 20220823 10
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Project description:BACKGROUND: Aberrant and non-functional RHD alleles are much more frequent in Africans than in Europeans. The DAU cluster of RHD alleles exemplifies that the alleles frequent in Africans have evaded recognition until recently. A comprehensive survey of RHD alleles in any African population was lacking. RESULTS: We surveyed the molecular structure and frequency of RHD alleles in Mali (West Africa) by evaluating 116 haplotypes. Only 69% could be attributed to standard RHD (55%) or the RHD deletion (14%). The aberrant RHD allele DAU-0 was predicted for 19%, RHDPsi for 7% and Ccdes for 4% of all haplotypes. DAU-3 and the new RHD allele RHD(L207F), dubbed DMA, were found in one haplotype each. A PCR-RFLP for the detection of the hybrid Rhesus box diagnostic for the RHD deletion in Europeans was false positive in 9 individuals, including all carriers of RHDPsi. Including two silent mutations and the RHD deletion, a total of 9 alleles could be differentiated. CONCLUSION: Besides standard RHD and the RHD deletion, DAU-0, RHDPsi and Ccdes are major alleles in Mali. Our survey proved that the most frequent alleles of West Africans have been recognized allowing to devise reliable genotyping and phenotyping strategies.
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Project description:According to recent work group recommendations, individuals with the serologic weak D phenotypes should be RHD genotyped and individuals with molecular weak D types 1, 2, 3, 4.0, or 4.1 should be treated as D+. We report an African American woman with a long-standing history of metrorrhagia, who presented for infertility evaluation. Blood grouping showed AB with a possible subgroup of A, based on mixed-field agglutination, and a serologic weak D phenotype. Results from routine red cell genotyping for the RHD gene was incongruent with the serologic RhCE phenotype. For the surgical procedure, the patient was hence scheduled to receive group AB, D- RBC transfusions. Subsequent molecular analysis identified the ABO*A2.01 and ABO*B.01 alleles for the ABO genotype and the novel RHD allele [NG_007494.1(RHD):c.611T>A] along with an RHD*09.01.02 allele for the RHD genotype. Using a panel of monoclonal anti-D reagents, we showed the novel RHD(I204K) allele to represent a serologic weak D phenotype, despite occurring as a compound heterozygote, designated RHD*weak D type 161 (RHD*01W.161). Individuals with a weak D type 4.2 allele are prone to anti-D immunization, while the immunization potential of novel RHD alleles is difficult to predict. For now, patients should be treated as D- in transfusion and pregnancy management, when they harbor a novel RHD allele along with any weak D allele other than weak D types 1, 2, 3, 4.0, or 4.1. This study exemplifies strategies for how and when a laboratory should proceed from routine genotyping to nucleotide sequencing before any decisions on transfusion practice is made.
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Project description:The Rh system, including the highly immunogenic D antigen, is one of the clinically most important blood group systems in transfusion medicine. Numerous alleles of the RHD gene are associated with variant RhD phenotypes. In case of Rh incompatibility, some of them can induce hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. Thus, accurate blood group diagnostics are critical for safe transfusion therapy. We characterized phenotypes of four individuals revealing weakened D expression during routine pre-transfusion testing. Standard gel card matrix techniques with monoclonal and polyclonal anti-D antibodies were used for serological typing, complemented using D epitope and antigen density analysis. Genotyping employing PCR with sequence-specific primers, genomic and allele-specific Sanger sequencing and in silico protein analysis were performed. Four novel RHD alleles associated with weak D or partial D phenotypes were identified. One of the mutations is predicted to disrupt the terminal stop codon and result in an elongated translation of the mutant D protein that phenotypically exhibits a loss of D epitopes. Furthermore, a hybrid gene formed with the homologue RHCE gene is described. The presented data enhances the understanding of the Rh system and may contribute to continued advances in blood group diagnostics.
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Project description:RHD del28Phe encoded by a novel in frame deletion in Exon 1 resulting in a weak D phenotype
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Project description:The expression of voltage-gated sodium channels is regulated at multiple levels, and in this study we addressed the potential for alternative splicing of the Na(v)1.2, Na(v)1.3, Na(v)1.6 and Na(v)1.7 mRNAs. We isolated novel mRNA isoforms of Na(v)1.2 and Na(v)1.3 from adult mouse and rat dorsal root ganglia (DRG), Na(v)1.3 and Na(v)1.7 from adult mouse brain, and Na(v)1.7 from neonatal rat brain. These alternatively spliced isoforms introduce an additional exon (Na(v)1.2 exon 17A and topologically equivalent Na(v)1.7 exon 16A) or exon pair (Na(v)1.3 exons 17A and 17B) that contain an in-frame stop codon and result in predicted two-domain, truncated proteins. The mouse and rat orthologous exon sequences are highly conserved (94-100% identities), as are the paralogous Na(v)1.2 and Na(v)1.3 exons (93% identity in mouse) to which the Na(v)1.7 exon has only 60% identity. Previously, Na(v)1.3 mRNA has been shown to be upregulated in rat DRG following peripheral nerve injury, unlike the downregulation of all other sodium channel transcripts. Here we show that the expression of Na(v)1.3 mRNA containing exons 17A and 17B is unchanged in mouse following peripheral nerve injury (axotomy), whereas total Na(v)1.3 mRNA expression is upregulated by 33% (P=0.003), suggesting differential regulation of the alternatively spliced transcripts. The alternatively spliced rodent exon sequences are highly conserved in both the human and chicken genomes, with 77-89% and 72-76% identities to mouse, respectively. The widespread conservation of these sequences strongly suggests an additional level of regulation in the expression of these channels, that is also tissue-specific.
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Project description:The Rh blood group system (ISBT004) is the second most important blood group after ABO and is the most polymorphic one, with 55 antigens encoded by 2 genes, RHD and RHCE This research uses next-generation sequencing (NGS) to sequence the complete RHD gene by amplifying the whole gene using overlapping long-range polymerase chain reaction (LR-PCR) amplicons. The aim was to study different RHD alleles present in the population to establish reference RHD allele sequences by using the analysis of intronic single-nucleotide polymorphisms (SNPs) and their correlation to a specific Rh haplotype. Genomic DNA samples (n = 69) from blood donors of different serologically predicted genotypes including R1R1 (DCe/DCe), R2R2 (DcE/DcE), R1R2 (DCe/DcE), R2RZ (DcE/DCE), R1r (DCe/dce), R2r (DcE/dce), and R0r (Dce/dce) were sequenced and data were then mapped to the human genome reference sequence hg38. We focused on the analysis of hemizygous samples, as these by definition will only have a single copy of RHD For the 69 samples sequenced, different exonic SNPs were detected that correlate with known variants. Multiple intronic SNPs were found in all samples: 21 intronic SNPs were present in all samples indicating their specificity to the RHD*DAU0 (RHD*10.00) haplotype which the hg38 reference sequence encodes. Twenty-three intronic SNPs were found to be R2 haplotype specific, and 15 were linked to R1, R0, and RZ haplotypes. In conclusion, intronic SNPs may represent a novel diagnostic approach to investigate known and novel variants of the RHD and RHCE genes, while being a useful approach to establish reference RHD allele sequences.
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Project description:circBax, a kind of circular RNA, encode novel protein
2024-11-27 | PXD058360 |