A new blood group system, RHAG: three antigens resulting from amino acid substitutions in the Rh-associated glycoprotein

Tilley, Louise; Green, C; Poole, Joyce; Gaskell, Alisa A.; Ridgwell, K.; Burton, Nick; Uchikawa, Makoto; Tsuneyama, Hatsue; Ogasawara, Kenichi; Akkök, Çiğdem Akalın; Daniels, Geoff

doi:10.1111/j.1423-0410.2009.01243.x

Cited by 41 publications

(65 citation statements)

References 36 publications

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“…Rh null red cells are stomatocytic and most individuals with Rh null have a compensated haemolytic anaemia, which may be severe enough to merit splenectomy. Homozygosity for rif-Zahar et al 1996), in addition to the presence of a low frequency antigen on RhAG (Tilley et al 2009). An X-linked gene, XK, produces the Xk protein and Kx (XK1) antigen.…”

Section: Null and Mod Phenotypesmentioning

confidence: 93%

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The molecular genetics of blood group polymorphism

Daniels

2009

Hum Genet

110

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Over 300 blood group specificities on red cells have been identified, many of which are polymorphic. The molecular mechanisms responsible for these polymorphisms are diverse, though many simply represent single nucleotide polymorphisms (SNPs). Other mechanisms include the following: gene deletion; single nucleotide deletion and sequence duplication, which introduce reading-frame shifts; nonsense mutation; intergenic recombination between closely linked genes, giving rise to hybrid genes and hybrid proteins; and a SNP in the promoter region of a blood group gene. Examples of these various genetic mechanisms are taken from the ABO, Rh, Kell, and Duffy blood group systems. Null phenotypes, in which no antigens of a blood group system are expressed, are not generally polymorphic, but provide good examples of the effect of inactivating mutations on blood group expression. As natural human 'knock-outs', null phenotypes provide useful clues to the functions of blood group antigens. Knowledge of the molecular backgrounds of blood group polymorphisms provides a means to predict blood group phenotypes from genomic DNA. This has two main applications in transfusion medicine: determination of foetal blood groups to assess whether the foetus is at risk from haemolytic disease and ascertainment of blood group phenotypes in multiply transfused, transfusion-dependent patients, where serological tests are precluded by the presence of donor red cells. Other applications are being developed for the future.

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Section: Null and Mod Phenotypesmentioning

confidence: 93%

“…4). RhAG, which expresses antigens of the RHAG blood group system (Tilley et al 2009), has sequence and conformational similarities to the Rh proteins, but has a single N-linked oligosaccharide chain on its Wrst extracellular loop. Like RHD and RHCE, RHAG comprises ten exons and is on chromosome 6 (Lögdberg et al 2005).…”

Section: The Rh Blood Group Systemmentioning

confidence: 99%

The molecular genetics of blood group polymorphism

Daniels

2009

Hum Genet

110

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“…In contrast, genetic mutations of RHAG (Fig. 6b, lower) cause recessive Rh deficiency syndrome (regulator type Rh null or Rh mod ) [31][32][33][34][35][36][37]146], or dominant over-hydrated hereditary stomatocytosis (OHSt) showing increased permeability to nomovalent cations [147]. The two genetic disorders show mild chronic hemolytic anemia and share some phenotypic features with other forms of hereditary stomatocytosis [148].…”

Section: The Rh Gene Family and Human Disease Associationsmentioning

confidence: 99%

The Rh protein family: gene evolution, membrane biology, and disease association

Huang

2009

Cell. Mol. Life Sci.

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The Rh (Rhesus) genes encode a family of conserved proteins that share a structural fold of 12 transmembrane helices with members of the major facilitator superfamily. Interest in this family has arisen from the discovery of Rh factor's involvement in hemolytic disease in the fetus and newborn, and of its homologs widely expressed in epithelial tissues. The Rh factor and Rh-associated glycoprotein (RhAG), with epithelial cousins RhBG and RhCG, form four subgroups conferring upon vertebrates a genealogical commonality. The past decade has heralded significant advances in understanding the phylogenetics, allelic diversity, crystal structure, and biological function of Rh proteins. This review describes recent progress on this family and the molecular insights gleaned from its gene evolution, membrane biology, and disease association. The focus is on its long evolutionary history and surprising structural conservation from prokaryotes to humans, pointing to the importance of its functional role, related to but distinct from ammonium transport proteins.

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“…Over 20 different RHAG alleles have been associated with a complete absence or a severe reduction of Rh and associated antigens 7. Mutations in the Rh complex are usually accompanied by decreased RhAG macrocomplex components CD47, LW and U antigen 8. We have seen the expression of CD47 on erythrocytes of the patient.…”

Section: Next-generation Sequencingmentioning

confidence: 70%

Overhydrated stomatocytosis associated with a complexRHAGgenotype including a novelde novomutation

et al. 2018

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Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the gene. We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis. Extensive haemolytic work-up including flow cytometry for eosin-5'-maleimide and CD47 expression levels was carried out. Targeted resequencing revealed two probably causative heterozygous mutations in (Leu336Ser and Ile149Met) and one heterozygous mutation in (Glu1046Lys) involvement was confirmed by decreased RhAG macrocomplex component indicated by the reduced CD47 expression on erythrocytes. analysis concordantly flagged:Leu336Ser and :Glu1046Lys as likely deleterious mutation, whereas:Ile149Met was reported as likely neutral by PROVEAN. Family screening by Sanger sequencing revealed :Leu336Ser in a mother and:Glu1046Lys in a father who were both asymptomatic, excluding them as causative dominant events, thus establishing :Ile149Met, novel mutation as probably causative. This case illustrates the importance of family screening in interpreting next-generation sequencing (NGS) data, as in silico analysis alone can be misleading. Erudite generation of diagnostic possibilities based on a thorough baseline clinical and laboratory work-up remains as important as ever, even as NGS brings about a paradigm shift in the diagnostic work-up of rare haemolytic anaemias.

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A new blood group system, RHAG: three antigens resulting from amino acid substitutions in the Rh-associated glycoprotein

Abstract: The three red cell antigens encoded by RHAG form the RHAG blood group system: Duclos is RHAG1 (030001); Ol(a) is RHAG2 (030002); and DSLK is provisionally RHAG3 (030003).

Cited by 41 publications

References 36 publications

The molecular genetics of blood group polymorphism

The molecular genetics of blood group polymorphism

The Rh protein family: gene evolution, membrane biology, and disease association

Overhydrated stomatocytosis associated with a complexRHAGgenotype including a novelde novomutation

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