The Dombrock blood group system: a review.
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Blood Group Antigens↗
Biomedical subjects
Marion E Reid
Publications and source records attributed to Marion E Reid.
GUTI: a new antigen in the Cromer blood group system.
BACKGROUND: The Cromer blood group system consists of seven high-incidence and three low-incidence antigens carried on decay-accelerating factor (DAF). This report describes the identification and characterization of a new Cromer high-incidence antigen, named GUTI. STUDY DESIGN AND METHODS: RT-PCR and sequence analysis were performed on cDNA prepared from a Chilean donor whose serum contained the alloantibody (anti-GUTI). Based on the observed point mutation, a PCR-RFLP assay using MaeII was developed. To map the epitope, DAF-deletion mutants were tested by immunoblotting with anti-GUTI. RESULTS: Sequence analysis revealed a substitution of 719G>A in DAF in the proband. The proband's parents and two daughters were heterozygotes for 719G>A, one sister whose RBCs typed GUTI- was homozygous for 719A, and one sister had the wild-type DAF (719G). Seven additional heterozygote samples were identified among 214 Chileans. No heterozygotes were found in 197 New York donors. Analysis using DAF-deletion mutants showed the antigenic determinant to be within short consensus repeat (SCR) 4. CONCLUSION: This study describes a novel high- incidence antigen (GUTI) in the Cromer blood group system characterized by the amino acid arginine at position 206 in SCR4 of DAF. The GUTI-negative proband has a substitution mutation that predicts for histidine at this position.
Adult↗
Mutations that diminish expression of Kell surface protein and lead to the Kmod RBC phenotype.
BACKGROUND: Kmod is an inherited rare RBC phenotype characterized by weak but detectable expression of high-incidence Kell antigens. STUDY DESIGN AND METHODS: The 19 exons and the intron-exon regions of the KEL gene from four unrelated Kmod individuals were sequenced and compared to wild-type KEL. To study the mechanisms by which the mutations result in depression of Kell antigens, mutant and wild-type Kell proteins were expressed in 293T cells and the amounts of protein present on the cell surface were determined. RESULTS: The following point mutations were identified: Kmod-1, homozygous 1208G>A, S363N; Kmod-2, heterozygous, 1208G>A, S363N and 2150 A>G, Y677C; Kmod-3 (previously classified as KEL:-13), heterozygous 1106T>C, L329P and 1716G>A, W532Stop; Kmod-4, heterozygous, 2227G>A, G703R and a silent 1839C>T mutation. In transfected 293T cells, fewer G703R and L329P mutant Kell proteins were transported to the cell surface compared with wild-type Kell protein, and there was no detectable Y677C mutant Kell protein. Previously, it was shown that that S363N Kell protein was not detected on the cell surface. CONCLUSION: Different point mutations, causing amino acid substitutions and presumably altering protein conformation, inhibit transport of the mutant Kell proteins to the cell surface. The different mutations leading to the Kmod phenotype explain why anti-Ku made by persons with the Kmod phenotype are not mutually compatible.
Amino Acid Substitution↗
The molecular genetics of the human I locus and molecular background explain the partial association of the adult i phenotype with congenital cataracts.
The human i and I antigens are characterized as linear and branched repeats of N-acetyllactosamine, respectively. Conversion of the i to the I structure requires I-branching beta-1,6-N-acetylglucosaminyltransferase activity. It has been noted that the null phenotype of I, the adult i phenotype, is associated with congenital cataracts in Asians. Previously, the identification of molecular changes in the IGnT gene, associated with the adult i phenotype, has been reported. In the present study, we demonstrate that the human I locus expresses 3 IGnT forms, designated IGnTA, IGnTB, and IGnTC, which have different exon 1, but identical exons 2 and 3, coding regions. The molecular genetics proposed for the I locus offer a new perspective on the formation and expression of the I antigen in different cells and provide insight into the questions derived from investigation of the adult i phenotype. Molecular genetic analyses of the I loci of the 2 adult i groups, with and without congenital cataracts, were performed, and enzyme function assays and expression patterns for the 3 IGnT transcripts in reticulocytes and lens-epithelium cells were analyzed. The results suggest a molecular genetic mechanism that may explain the partial association of the adult i phenotype with congenital cataracts and indicate that a defect in the I locus may lead directly to the development of congenital cataracts. The results also suggest that the human blood group I gene should be reassigned to the IGnTC form, not the IGnTB form, as described previously.
Adult↗
Two new molecular bases for the Dombrock null phenotype.
Red blood cells (RBCs) with the Do(null) phenotype lack all antigens in the Dombrock blood group system, i.e. Do(a), Do(b), Gy(a), Hy and Jo(a). Sequence analysis of DNA from one proband with the Do(null) phenotype revealed a single nucleotide mutation of t to c in the donor splice site of DO (IVS1 + 2t > c), with outsplicing of exon 2. Analysis of a second proband revealed a homozygous nonsense mutation 442 C > T in exon 2 predicting a premature stop codon (Gln148 Stop). The molecular bases described in these two probands provide an explanation for the lack of Do glycoprotein on their RBCs.
Base Sequence↗
Insights into the Holley- and Joseph- phenotypes.
BACKGROUND: The Dombrock blood group system consists of two antithetical antigens (Do(a) and Do(b)) and three high-incidence antigens (Gregory [Gy(a)], Holley [Hy], and Joseph [Jo(a)]). Hy and Jo(a) have an unusual phenotypic relationship. All Hy- RBCs are Jo(a-), but not all Jo(a-) RBCs are Hy-. The molecular background associated with Hy- and Jo(a-) phenotypes is reported. STUDY DESIGN AND METHODS: DNA from 18 probands with Gy(a+(w)) Hy- Jo(a-) RBCs (Hy- phenotype) and from 13 probands with Gy(a+) Hy+(w) Jo(a-) RBCs (Jo[a-] phenotype) was tested. RESULTS: Sequencing and PCR-RFLP revealed 323 G>T (Gly 108Val) and 378 T>C (silent mutation) changes on a DOB background (HY) associated with the Hy- samples. The sister of the original Hy- proband and the majority of samples had an additional mutation of 898 C>G (Leu300Val) (HY1); others had 898C (300Leu) (HY2). In the Jo(a-) phenotype, there is a 350 C>T (Thr1 17Ile) and a 378 C>T (silent mutation) change on a DOA background (JO). CONCLUSION: The results provide an explanation for the variation in typing results in antibody producers. The ablation of Jo(a) in the Hy- phenotype and the weakening of Hy in the Jo(a-) phenotype may be due to the close proximity of these antigens. The 898 C>G mutation, within the sequence motif for glycosylphosphatidylinositol linkage, may cause reduced efficiency of anchoring the protein to the RBC membrane, thereby weakening the expression of Gy(a) and Do(b).
Amino Acid Sequence↗
Point mutations causing the McLeod phenotype.
BACKGROUND: The McLeod phenotype is defined by absence of Kx, weakening of Kell system antigens, and acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities. Gene deletions, insertions, and point mutations that affect RNA splicing or that lead to premature stop codons have been reported to cause the McLeod phenotype. The McLeod phenotype may also be caused by mutations at a different splice site and by a novel mutation encoding an amino acid substitution that prevents transport to the cell surface. STUDY DESIGN AND METHODS: The coding and flanking intron regions of XK from four male, unrelated individuals with the McLeod phenotype and non-chronic granulomatous disease were sequenced and compared with the wild type sequence. Genomic DNA was amplified by PCR, and the products were sequenced. In one case, the mutant cDNA was expressed in a heterologous cell, and cell surface expression was determined. RESULTS: Three individuals with the McLeod phenotype had mutations that disrupted conserved GT sequences present at RNA splice sites. Two of them had G>C mutations at the 5' splice site of intron 1, and one had a G>A mutation at the 5' splice site of intron 2. One person with the McLeod phenotype had a 746C>G mutation in exon 3 encoding an R222G substitution. In a transfected cell, the expressed protein from the latter mutant did not travel to the cell surface. CONCLUSION: The McLeod phenotype may be caused by several different mutations.
Acanthocytes↗
The McLeod syndrome: an example of the value of integrating clinical and molecular studies.
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Acanthocytes↗
Cloning and genetic characterization of blood group carrier molecules and antigens.
Based on the astounding pace of growth in the field of molecular biology over the last 2 decades, we are now able to consider the allogenicity of transfused blood products in genetic terms. In this sense, the allogenic barriers to the transfusion-based transplantation are defined by differences between those portions of the donor and recipient genomes that define the antigenicity and immune response to transfused cells. The genetic basis of the major histocompatibility complex barrier described earlier is because of well-characterized transcription from a polymorphic locus on chromosome 6 in nonerythroid cells. In contrast, the allo-barrier of ABO-matched RBC transfusion is the result of differences in over 2 dozen independent genes expressed during erythropoiesis that encode a wide variety of molecules important in membrane biology. Variability in the structure of those genes among separate donors often provides the molecular basis of many blood group antigens and phenotypes. This article reviews our current knowledge of the human blood group systems in genetic terms, focusing on strategies used to identify the relevant genes and their polymorphisms.
Animals↗
Molecular approaches to blood group identification.
Allogeneic barriers to transfusion are caused by differences between those portions of the donor and recipient genomes that define the antigenicity and immune response to the transfused cells. Historically, a blood group antigen was identified when an immune response (alloantibody) was detected by hemagglutination in the serum of a transfused patient. There has been an astounding pace of growth over the past two decades in the field of molecular biology techniques and even more recently in the understanding of the basis of many blood group antigens and phenotypes. Identification of blood group antigens can now be performed in genetic terms, and identification of blood group antibodies can be performed using molecular approaches. This knowledge is being applied to help resolve some long-standing clinical problems that cannot be resolved by classical hemagglutination. This article reviews knowledge of molecular approaches for identifying blood group antigens and antibodies as applied to transfusion medicine practice.
Animals↗
DNA analysis to find rare blood donors when antisera is not available.
In order to screen for antigen-negative blood donors, it is necessary to have appropriate, potent antisera in sufficient volume. Anti-Do(a) and anti-Do(b) are notoriously weakly reactive antibodies, available only in small volumes, usually in sera containing other alloantibodies, and often deteriorate on storage. Thus, it has not been possible to test large numbers of blood samples to find Do (a-) or Do (b-) blood donors. At the NYBC, we now type selected donors for DOA and DOB by DNA analysis. Initially, we tested DNA prepared from donors who had been typed by hemagglutination for one or both antigens. We found that four donors, whose RBCs previously typed as Do (a+b-), had both DOA and DOB alleles, and when retested, the RBCs were Do (a+b+w). We have now tested over 300 donors for DO by PCR-RFLP using either Eam1105 I or BseRI restriction enzymes. Blood from DOA/DOA donors has survived better than "crossmatch compatible" blood for patients with anti-Do(b) and such results suggest that anti-Do(b) is a more frequent cause of transfusion reactions than reported. Furthermore, we have demonstrated that PCR-RFLP can be used to screen for antigen-negative donors in other blood group systems when appropriate antisera are not available. When interpreting the results, it is important to remember that the genotype may not reflect the phenotype. Our strategy has been to perform DNA analysis for the DO alleles on those donors who have been shown by hemagglutination to lack antigens corresponding to multiple alloantibodies in patients' plasma. In this way, we have been able to supply rare blood to numerous patients, whose serum contained at least 5 additional alloantibodies of clinical significance.
Blood Donors↗
Molecular biology in transfusion medicine: current applications and future practice.
Alloantibodies to blood group antigens are produced because there are differences between the blood group antigens on recipient and donor (or mother and fetus) red blood cells. Historically and currently, blood group antibodies and antigens are detected by hemagglutination, which can require considerable skill. Over the past 2 decades, there has been an astounding pace of growth in the field of molecular biology techniques and even more recently in the understanding of the basis of many blood group antigens and phenotypes. Thus, we are now able to consider identification of blood group antigens in genetic terms and identification of blood group antibodies using molecular approaches. Indeed, this knowledge is being applied to help resolve some long-standing clinical problems that cannot be resolved by classic hemagglutination. This article reviews our current knowledge of molecular approaches for identifying blood group antigens and antibodies as applied to transfusion medicine.
Blood Group Antigens↗