Weak D and DEL alleles detected by routine SNaPshot genotyping: identification of four novel RHD alleles

Silvy, Monique; Simon, Sophie; Gouvitsos, Julia; Cristofaro, Julie Di; Ferrera, Virginie; Chiaroni, Jacques; Bailly, Pascal

doi:10.1111/j.1537-2995.2010.02830.x

Cited by 35 publications

(41 citation statements)

References 40 publications

(57 reference statements)

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“…The C‐terminal cytoplasmic domain of RhD has been experimentally demonstrated to interact with Domain 2 of ankyrin‐R 16 , and multiple amino acid substitutions (including P411 that would be removed by the large deletion) introduced into the C‐terminal cytoplasmic domain of RhD by directed mutagenesis have been reported to be associated with a reduced expression of the RhD antigen in model systems 17 . In addition, one RHD missense mutation, F410V, which would also be removed by the deletion, was reported to be associated with a weak D phenotype 18,19 . Thus, the replacement of eight amino acids by another four ones in the extreme C‐terminal end of RhD (Fig.…”

Section: Discussionmentioning

confidence: 99%

Weak D caused by a founder deletion in the RHD gene

et al. 2012

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The currently reported deletion was derived from a common founder. This deletion appears to represent not only the first large deletion associated with weak D but also the weakest of weak D alleles so far reported. This highly unusual genotype-phenotype relationship may be attributable to the additive effect of three distinct mechanisms that affect mRNA formation, mRNA stability, and RhD/ankyrin-R interaction, respectively.

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Section: Discussionmentioning

confidence: 99%

Weak D caused by a founder deletion in the RHD gene

et al. 2012

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“…An up‐to‐date review of the literature and the RhesusBase was performed . On the basis of their position relative to the constitutive SSs, 15 variations of the RHD gene, including eight exonic (i.e., first, antepenultimate and penultimate position of exons) and seven intronic variants were selected for functional analysis (Table ).…”

Section: Methodsmentioning

confidence: 99%

Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype

Raud

Gourlaouen

et al. 2019

Transfusion

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BACKGROUND We previously showed that several variations in the RHD gene, including synonymous changes, can be classified as splice site variants and may play a direct role in D variant phenotype expression. We sought to extend our study to additional candidates, notably in the first and last exons of the gene, by engineering a novel universal splice reporting vector, i.e., minigene. STUDY DESIGN AND METHODS Our previous plasmid construct was modified to allow subcloning of any exon(s) of interest for assessing effect of variations on splicing. Seventeen novel and/or uncharacterized variations of the RHD gene were selected for the study and tested in our novel model. RESULTS We engineered and validated a novel universal minigene for assessing virtually any variations of interest for splicing defect. Of the 17 variants tested in the novel model, 11 were shown to alter splicing either totally or partially, including the silent c.1065C>T variation, which induces major skipping of exon 7, and may therefore be responsible for reducing D antigen expression. We also showed that while all three missense variations c.1154G>C, c.1154G>T, and c.1154G>A in exon 9 are splice site variants, splicing is differentially altered and D‐negative phenotype observed in the presence of the latter substitution is likely due to a defect in RhD protein folding. CONCLUSION Overall, we hypothesize that splicing alteration is likely to be a common mechanism of D phenotype variation that has been underestimated so far. Further large‐scale studies are necessary to demonstrate this statement definitely.

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“…Finally, we did not find any variants in the entire coding sequences, the exon‐intron boundaries, and the proximal 5′‐UTR and 3′‐UTR of the RHD gene in 6.3% (n = 51) of the 806 samples analyzed. (A recent study reported that in three of 23 samples in which a SNaPshot assay failed to detect mutations, no nucleotide changes in the full coding sequence of the RHD gene were found by sequencing 8 …”

Section: Conclusion and Perspectivementioning

confidence: 99%

“…Two particular concerns, namely, 1) that red blood cells (RBCs) of these phenotypes may cause anti‐D immunization when transfused to D– recipients 3‐7 and 2) that serologic determination of these phenotypes are often not clear cut, make genetic analysis of the RHD gene highly desirable. To date, more than 100 weak and partial D alleles have been registered in the Rhesus Site, with new ones being steadily reported 8,9 . Here, we report 17 novel RHD alleles resulting from a systematic variant screening in a large cohort of subjects with doubtful D phenotypes.…”

mentioning

confidence: 91%