The Cromer blood group system antigens are carried on CD55 (also known as DAF), a molecule that continues to demonstrate increasing polymorphism. CD55 is an important regulatory protein within the complement cascade and has increasingly been shown to play a role in hemostasis. CD55 is one of a few blood group–carrying proteins that are attached to the red blood cell (RBC) membrane through a glycosylphosphatidylinositol (GPI) linkage, and thus the Cromer “null” (IFC‒, Inab) phenotype arises not only from variation in the CD55 coding sequence but also as a consequence of disease, such as paroxysmal nocturnal hemoglobinuria (PNH).
One of the fascinating observations regarding the nucleotide variation giving rise to Cromer blood group system antigens is that many of them have been identified in a unique folk group. With the major advances in genome analysis worldwide, we can now see that our serologic discoveries have specifically captured this variation long before it was seen as a regional marker.
Since the publication of the original review, 1 the Cromer blood group system has continued to expand, and a further five high-prevalence antigens have been described (Table 1).
High-prevalence antigens of the Cromer blood group system: molecular basis and distribution of the antigen-negative phenotype
Number | Name | Nucleotide change | Exon | Amino acid change | Reference | rs number* | Negative phenotype identified in | gnomAD † frequency of the variant allele (≥0.01%) |
---|---|---|---|---|---|---|---|---|
CROM1 | Cra | c.679G>C | 6 | p.Ala227Pro | 2 | rs60822373 | African Americans | African 2% |
CROM5 | Dra | c.596C>T | 5 | p.Ser199Leu | 3 | rs1135402914 | Uzbekistani Jewish, Japanese | None |
CROM6 | Esa | c.239T>A | 2 | p.Ile80Asn | 4 | rs776347919 | Mexicans, African Americans | None |
CROM10 | UMC | c.749C>T | 6 | p.Thr250Met | 5 | rs566298946 | Japanese | East Asian 0.1% |
CROM11 | GUTI | c.719G>A | 6 | p.Arg240His | 6 | rs199705465 | Native Chileans |
Finn 0.02% |
CROM12 | SERF | c.647C>T | 5 | p.Pro216Leu | 7 | rs144692928 | Thais | South Asian 0.1% |
CROM13 | ZENA | c.726T>G | 6 | p.His242Gln | 7 | rs769586650 | Turkish Syrians | None |
CROM14 | CROV | c.466G>A | 3 | p.Glu156Lys | 7 | No rs | Croatians | Data not available |
CROM15 | CRAM | c.740A>G | 6 | p.Gln247Arg | 7 | No rs | Somalians | Data not available |
CROM16 | CROZ | c.389G>A | 3 | p.Arg130His | 8 | rs756646491 | Australians | None |
CROM17 | CRUE | c.650T>G | 5 | p.Leu217Trp | 9 | rs567156112 | Thais | East Asian 0.1% |
CROM18 | CRAG | c.173A>G | 2 | p.Asp58Gly | 10 | No rs | Greeks | Data not available |
CROM19 | CROK | c. 245T>C | 2 | p.Leu82Pro | 11 | No rs | Israeli Druze | Data not available |
CROM20 | CORS | c.713G>A | 6 | p.Gly238Glu | 12 | No rs | French Corsicans | Data not available |
*Reference single nucleotide polymorphism cluster identification number.
†Genome Aggregation Database.
An antibody reactive with all RBCs except for the patient’s own and IFC‒ RBCs was identified in the plasma of an Australian woman. Molecular analysis of
The antigen CRUE (CROM17) was assigned after a classic serologic investigation of an antibody in the plasma of a Thai woman. The patient’s RBCs reacted somewhat more weakly with antisera to other Cromer antigens, and molecular investigation revealed that she was heterozygous for two novel
CRAG (CROM18) was described following the identification of a Cromer-related antibody in the plasma of an elderly Greek woman. DNA analysis revealed homozygosity for c.173A>G, which encodes an amino acid substitution of p.Asp58Gly carried by CCP1. 10
The CROK antigen (CROM19) is somewhat of a conundrum. The antibody that led to the discovery of this antigen was originally defined as anti-IFC, that is, it reacted with all RBCs except for those lacking CD55 (IFC‒ or Inab phenotype), but it reacted only weakly with WES(a+b‒) RBCs. The patient’s RBCs were negative with all available antibodies to Cromer antigens. The weaker reactivity with WES(a+b‒) RBCs could be explained in part by the molecular basis, which showed that the proband (of Druze origin) was homozygous for
Antithetical antigens in the Cromer blood group system: molecular basis and distribution of the low-prevalence antigen
High-prevalence antigen number | Name | Low-prevalence antigen number | Name | Nucleotide change | Exon | Amino acid change | Reference | rs number* | Low-prevalence antigen identified in | gnomAD † frequency of the low-prevalence allele (>0.01%) |
---|---|---|---|---|---|---|---|---|---|---|
CROM2 | Tc a | CROM3 | Tcb | c.155G>T | 2 | p.Arg52Leu | 2 | rs28371588 | African Americans | African 2.6% |
CROM4 | Tcc | c.155G>C | p.Arg52Pro | 4 | Europeans | European 0.03% | ||||
CROM9 | WESb | CROM8 | WESa | c.245T>G | 2 | p.Leu82Arg | 4 | rs147474393 | African Americans, Finns | African 0.3% |
*Reference single nucleotide polymorphism cluster identification number.
†Genome Aggregation Database.
A long-standing serologic mystery was solved by whole exome sequencing on DNA samples from a 103-year-old Corsican woman and her son.
12
Analysis revealed homozygosity in the patient’s
Three new silenced
Molecular bases for the new CD55null (IFC-, Inab phenotype) alleles
ISBT allele name | Nucleotide change | Exon | Amino acid change | Reference | rs number † | Null phenotype identified in | Occurrence in gnomAD ‡ |
---|---|---|---|---|---|---|---|
|
c.366 367insA | 3 | p.Thr123Asnfs*6 | 8 |
No rs | Moroccans | |
|
c.148G>T | 2 | p.Glu50Ter | 13 | rs773074921 | Pakistanis | 3/30,616 alleles in South Asian population only |
|
c.639G>A | 5 | p.Trp213Ter | 9 | rs1391706310 | Thais | 3/18,392 alleles in East Asian population only |
Not assigned | c.149_150delAAinsCCTT | 2 | p.Glu50Alafs*12 | 19 | rs1135402916 | Turks | No data |
c.109delG | 2 | p.Gly37Alafs*24 | rs1135402915 | Turks, Syrians | No data | ||
c.800G>C | 6 | p.Cys267Ser | rs1135402917 | Turks | No data | ||
c.287-1G>A | 3 | Exon skipping | rs1135402918 | Turks | No data |
ISBT = International Society of Blood Transfusion.
†Reference single nucleotide polymorphism cluster identification number.
‡Genome Aggregation Database.
Anti-IFC in a young Moroccan woman with a history of miscarriages led to the identification of homozygosity for a single nucleotide insertion c.366_367insA in
Another case of anti-IFC was identified in a young Kashmiri woman following the birth of her first child. She had a history of two spontaneous abortions, although the underlying cause was unknown. Her serologic picture was complicated, however, because her RBCs not only lacked CD55 but were also Yt(a‒) and MER2‒. DNA analysis revealed homozygosity for two novel nucleotide changes, c.147G>A (silent), and c.148G>T, predicted to encode p.Glu50Stop. 13
The third Cromer null allele to have been described since the original review was identified in the CRUE‒ proposita described earlier, who was heterozygous for an allele carrying the mutation c.639C>A that introduced a novel stop codon: p.Trp213Ter. 9
In all of the cases described herein, there had been an immunizing event—pregnancy, transfusion, or both—that was the likely cause of antibody production. However, the clinical significance of the antibodies, with regard to transfusion where it had occurred, was unremarkable enough not to be commented on in the reports. It has been well documented that antibodies to Cromer blood group system antigens decrease in titer over the duration of a pregnancy, and this finding has been attributed to adsorption by the placenta. 14,15
Of interest, while reviewing the literature, was the fact that the two young women in whom new null alleles were identified had both suffered from two or more miscarriages. 9,13 Although a comprehensive review of the role of CD55 in pregnancy is beyond the scope of this blood group system update, significantly low expression levels of CD55 mRNA were identified in women suffering from spontaneous abortion in one study. 16 Complement regulators including CD55 are expressed early on the syncytiotrophoblast and are thought to be important in protecting the developing fetus from complement-mediated attack. Furthermore, it has been shown that spontaneous abortion or early termination occurs in almost half of women with PNH, who lack the GPI-linked complement regulators, CD55 and CD59 (reviewed in Regal et al. 17 ).
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