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1.
Immunohematology ; 30(1): 11-3, 2014.
Article in English | MEDLINE | ID: mdl-25238244

ABSTRACT

The red blood cells (RBCs) of most adult individuals display an I+i- phenotype, whereas those of newborns and some rare adult individuals are typed as I-i+. The phenotype in the latter category, designated as adult i, is under genetic influence as the RBCs of I+i+ individuals display strengths of I and i antigen expression intermediate to that of ordinary adults and ii-adults. As there was no information on the occurrence of adult i phenotype in the Indian population, the present study was undertaken. The RBCs of randomly selected subjects were screened with anti-I and anti-i reagents by a saline tube technique at 220C. Individuals with unusual I and i antigen reactivity patterns were further tested by a semi-quantitative method with a battery of anti-I and anti-i reagents, followed by family studies. Three of the 5864 donors tested showed an elevated strength of i antigen. Further study revealed an intermediate strength of both I and i antigens compared with those on RBCs from adult and cord blood samples. All three probands came from an ethnic Parsi community. The phenotype (referred to as I-int) was shown to be inherited, being passed through two generations, but none of the members of the families had displayed an adult i phenotype. The I-int phenotype detected showed an ethnic association because all three subjects belonged to an endogamous Parsi community that has migrated to India some centuries ago from Persia, the present-day Iran.


Subject(s)
I Blood-Group System/analysis , Erythrocytes/chemistry , Ethnicity , Female , Humans , I Blood-Group System/genetics , India , Male , Pedigree , Phenotype
2.
Curr Opin Hematol ; 18(6): 421-6, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21912254

ABSTRACT

PURPOSE OF REVIEW: The molecular genetics of the blood group I system and the regulation mechanism for I antigen expression in postnatal red blood cells are intriguing. This review summarizes their elucidation and recent findings. RECENT FINDINGS: Accumulating data from the molecular analysis of individuals with the adult i phenotype supports the proposed molecular genetic mechanism for the partial association of the adult i phenotype with congenital cataracts. Recent investigations have shown that the regulation of I antigen formation during erythropoiesis is determined by transcription factor CCAAT/enhancer binding protein-α (C/EBPα) and the phosphorylation status of C/EBPα Ser-21 residue. SUMMARY: The human I locus is organized such that it has an uncommon genetic architecture and expresses three different I transcript forms. The results obtained from molecular analysis of two adult i groups, with and without congenital cataracts, demonstrate that the molecular background accounts for the partial association between these two traits and suggest that an I gene defect may lead directly to the development of congenital cataracts. Analysis of the regulation for I antigen expression shows that the regulation during erythropoiesis and granulopoiesis share a common mechanism, with dephosphorylation of the Ser-21 residue on C/EBPα playing the critical role.


Subject(s)
Erythropoiesis/physiology , Glycosphingolipids/metabolism , I Blood-Group System/genetics , I Blood-Group System/immunology , Leukopoiesis/physiology , Cataract/congenital , Cataract/immunology , Erythrocytes/metabolism , Erythropoiesis/genetics , Humans , Leukopoiesis/genetics
4.
Transfusion ; 46(11): 1982-7, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17076854

ABSTRACT

BACKGROUND: The adult i phenotype has been characterized as the presence of a very low level of I antigen but a high quantity of I antigen on red blood cells (RBCs). It has been noted that this rare phenotype is partially associated with congenital cataracts. It has been demonstrated that the human I locus expresses three IGnT forms, IGnTA, IGnTB, and IGnTC, and that the IGnTC gene is responsible for the I antigen expression on RBCs. This report describes molecular genetic analysis of a Taiwanese person with the adult i phenotype but without congenital cataracts. STUDY DESIGN AND METHODS: The five exon regions of the IGnT gene of the adult i individual were amplified by polymerase chain reaction (PCR) and cloned, and the sequences were determined. The activity of the IGnT enzyme expressed from the mutant IGnTC gene identified in this i adult was analyzed. RESULTS: The presented adult i individual possesses wild-type IGnTA and IGnTB genes but a mutant IGnTC gene with a 243T>A nucleotide substitution, which predicts an amino acid alteration of Asn81Lys. PCR-restriction fragment length polymorphism analysis has been used to show that this IGnTC*243A allele is uncommon in the general Taiwanese population. The activity of the IGnT enzyme expressed from the mutant IGnTC*243A gene was significantly reduced when compared with that expressed from the wild-type IGnTC gene. CONCLUSION: A novel IGnTC allele with a 243T>A missense mutation was demonstrated in our adult i Taiwanese without congenital cataracts. The molecular basis revealed for this adult i case agrees with the proposed molecular genetic mechanism, accounting for the partial association of the adult i phenotype with congenital cataracts.


Subject(s)
Alleles , Amino Acid Substitution , I Blood-Group System/genetics , Mutation, Missense , N-Acetylglucosaminyltransferases/genetics , Polymorphism, Restriction Fragment Length , Adult , Asian People , Cataract/congenital , Cataract/genetics , Female , Gene Expression , Humans , Isoenzymes/genetics , Male , Phenotype , Polymerase Chain Reaction , Taiwan
5.
Immunohematology ; 20(4): 249-52, 2004.
Article in English | MEDLINE | ID: mdl-15679458

ABSTRACT

Unlike most blood group antigen pairs, the I and i antigens are not antithetical (produced by allelic pairs) but, rather, they are reciprocal. The I antigen is formed by the action of an enzyme (a glycosyltransferase), which adds branches onto the i antigen. Thus, branched I antigen is formed at the expense of its precursor, the linear i antigen. The antigens are present on all blood cells and have a wide tissue distribution. Soluble I antigen is found in milk, saliva, and amniotic fluid, and a small amount is in plasma. The function of these antigens is unknown but the I antigen has a decreased expression and the i antigen has a concomitant increased expression in conditions that result in increased hematopoiesis. The gene encoding the branching transferase has been cloned and sequenced, and the mechanism underlying the i adult phenotype with and without association with cataracts has been elucidated.


Subject(s)
Cataract/immunology , I Blood-Group System/genetics , Carbohydrate Sequence , Cataract/congenital , Cataract/etiology , Glycosyltransferases/genetics , Glycosyltransferases/metabolism , Glycosyltransferases/physiology , Humans , I Blood-Group System/biosynthesis , I Blood-Group System/metabolism , Phenotype , Tissue Distribution
6.
Blood ; 101(6): 2081-8, 2003 Mar 15.
Article in English | MEDLINE | ID: mdl-12424189

ABSTRACT

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.


Subject(s)
Cataract/congenital , Cataract/genetics , I Blood-Group System/genetics , N-Acetylglucosaminyltransferases/genetics , Phenotype , Adult , Alleles , Amino Acid Sequence , Asian People , Chromosomes, Human, Pair 6 , DNA, Complementary/analysis , Humans , Isoenzymes/genetics , Lens, Crystalline/enzymology , Male , Molecular Sequence Data , Mutation , N-Acetylglucosaminyltransferases/chemistry , Polymorphism, Restriction Fragment Length , RNA, Messenger/analysis , Reticulocytes/enzymology , Reverse Transcriptase Polymerase Chain Reaction , Taiwan , White People
7.
Blood ; 98(13): 3840-5, 2001 Dec 15.
Article in English | MEDLINE | ID: mdl-11739194

ABSTRACT

The human blood group i and I antigens are characterized as linear and branched repeats of N-acetyllactosamine, respectively. Conversion of the i to the I structure requires the activity of I-branching beta-1,6-N-acetylglucosaminyltransferase (IGnT). Thus the blood group I gene is assigned to encode a beta-1,6-N-acetylglucosaminyltransferase; however, its identity has not been confirmed. The null phenotype of I, the adult i phenotype, provides a means to identify the I gene. Interestingly, the adult i phenotype has been noted to be associated with congenital cataracts in Asians. Molecular genetic studies of 3 adult i pedigrees are reported here. The results obtained on mutation detection within the 2 I-branching enzyme encoding genes, segregation analyses, and enzyme function assays identify molecular changes associated with the adult i phenotype. The adult i phenotype in 2 of the pedigrees studied resulted from 1043G-->A and 1148G-->A mutations, which predict Gly348Glu and Arg383His alterations, respectively, in the IGnT gene. These amino acid changes abolished the original GlcNAc-transferase activity. Deletion of the IGnT gene was observed in the person with adult i phenotype in the third pedigree. These findings suggest that the IGnT gene, first reported in 1993, is the candidate for the blood group I gene. Confirmation of the blood group I gene will further assist in the investigations of the molecular genetics that control I antigen expression in secretions and the molecular basis for the association of the adult i phenotype with congenital cataracts in Asians.


Subject(s)
Gene Expression , I Blood-Group System/genetics , N-Acetylglucosaminyltransferases/genetics , Phenotype , Adult , Asia , Cataract/congenital , Cataract/genetics , Cloning, Molecular , DNA Mutational Analysis , Gene Deletion , Gene Frequency , Genetic Linkage , Humans , Molecular Sequence Data , Mutation , Mutation, Missense , N-Acetylglucosaminyltransferases/metabolism , Pedigree , Polymorphism, Restriction Fragment Length , Reverse Transcriptase Polymerase Chain Reaction
8.
Scand J Immunol ; 42(1): 90-7, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7631150

ABSTRACT

We have sequenced the variable heavy chain regions of a number of VH4-21 encoded monoclonal IgM anti-Rh(D) antibodies produced in response to deliberate immunization. These were compared with the sequences of similarly encoded IgM anti-I cold agglutinins (CA) derived from patients with lympho-proliferative diseases. The anti-Rh(D) antibodies show evidence of clonal expansion and somatic diversification. Even though they are produced in response to an antigenic stimulus, they demonstrate limited hypermutation in the variable heavy chain (VH) segments and there is no evidence of selective pressure acting on the complementarity determining regions (CDRs). The CA demonstrate a higher rate of mutation and yet this results in a lower ratio of replacement to silent mutations (R:S) in the CDRs than seen in the anti-Rh(D) antibodies. It is not clear whether the different pattern of mutations seen in the CA is related to their auto-reactivity or their tumour origin. In both groups of antibodies the region encoded by the VH4-21 segment can be found in germline configuration at the amino-acid level indicating that other V-gene structures, i.e. light chains or CDRH3s, are crucial to the generation of either specificity. A role of the CDRH3 is indicated by the identification of a motif shared by four CAs and one Rh(D) antibody which also demonstrates CA activity independent of its anti-Rh(D) specificity. Amongst the anti-Rh(D) antibodies there seems to be an obligatory combination with VL having closest homology to the DPL16 germline segment indicating this as particularly important in generation anti-Rh(D) specificity.


Subject(s)
Autoantibodies/immunology , Immunoglobulin Heavy Chains/immunology , Immunoglobulin M/immunology , Immunoglobulin Variable Region/immunology , Isoantibodies/immunology , Agglutinins/immunology , Amino Acid Sequence , Antibodies, Monoclonal/immunology , Base Sequence , Carbohydrates/immunology , Cryoglobulins , Erythrocytes/immunology , Humans , I Blood-Group System/genetics , Immunoglobulin M/genetics , Isoantibodies/chemistry , Molecular Sequence Data , Mutation/genetics , Rh-Hr Blood-Group System/genetics , Rh-Hr Blood-Group System/immunology
9.
Vox Sang ; 68(4): 231-5, 1995.
Article in English | MEDLINE | ID: mdl-7660642

ABSTRACT

Most autoanti-red cell antibodies found in patients with cold agglutinin disease are specific for the I or i carbohydrate antigenic determinants. However, antibodies specific for other antigens such as Pr or Sa can also be found, and these are identified by their pattern of reactivity with enzyme-treated red cells. Recently, it has been shown that the vast majority of anti-Ii antibodies react with a monoclonal anti-idiotypic antibody (9G4); this reactivity arises from restriction of the immunoglobulin heavy chains used to encode the antibodies to a single VH4-21 gene, VH4-21. The 9G4 antibody appears specific for this gene product, and we have used it to analyse VH4-21 gene involvement in encoding a spectrum of red cell antibodies of various specificities. The results support the strong association between usage of this gene and anti-Ii specificity and indicate that it is not generally used by other specificities. In particular, it is striking that the unsubstituted type 2 oligosaccharide antigens (I and i) induce a highly restricted autoantibody response very different from that induced by the sialylated type 2 antigens (Sia-b, -1 and 1b). The 9G4 antibody therefore provides a simple tool for discrimination between these autoanti-red cell antibodies, which should be of use in red cell serology.


Subject(s)
Autoantibodies/genetics , Erythrocytes/immunology , I Blood-Group System/genetics , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Adult , Agglutinins/immunology , Antibodies, Anti-Idiotypic/genetics , Antibodies, Anti-Idiotypic/immunology , Antibodies, Monoclonal/immunology , Antibody Specificity/genetics , Antibody Specificity/immunology , Autoantibodies/immunology , Cryoglobulins , Enzyme-Linked Immunosorbent Assay/methods , Genes, Immunoglobulin , Hemagglutination Inhibition Tests , Humans , I Blood-Group System/immunology , Immunoglobulin Heavy Chains/immunology , Immunoglobulin Variable Region/immunology
10.
Genes Dev ; 7(3): 468-78, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8449405

ABSTRACT

The blood group i/I antigens were the first identified alloantigens that display a dramatic change during human development. The i and I antigens are determined by linear and branched poly-N-acetyllactosaminoglycans, respectively. In human erythrocytes during embryonic development, the fetal (i) antigen is replaced by the adult (I) antigen as a result of the appearance of a beta-1,6-N-acetylglucosaminyltransferase, the I-branching enzyme. Here, we report the cDNA cloning and expression of this branching enzyme that converts linear into branched poly-N-acetyllactosaminoglycans, thus introducing the I antigen in transfected cells. The cDNA sequence predicts a protein with type II membrane topology as has been found for all other mammalian glycosyltransferases cloned to date. The Chinese hamster ovary cells that stably express the isolated cDNA acquire I-branched structures as evidenced by the structural analysis of glycopeptides from these cells. Comparison of the amino acid sequence with those of other glycosyltransferases revealed that this I-branching enzyme and another beta-1,6-N-acetylglucosaminyltransferase that forms a branch in O-glycans are strongly homologous in the center of their putative catalytic domains. Moreover, the genes encoding these two beta-1,6-N-acetylglucosaminyltransferases were found to be located at the same locus on chromosome 9, band q21. These results indicate that the I-branching enzyme represents a member of a beta-1,6-N-acetylglucosaminyltransferase gene family of which expression is controlled by developmental programs.


Subject(s)
Chromosomes, Human, Pair 9 , DNA/genetics , I Blood-Group System/genetics , Isoantigens/genetics , Multigene Family , N-Acetylglucosaminyltransferases/genetics , Adult , Animals , CHO Cells , Carbohydrate Sequence , Chromosome Banding , Chromosome Mapping , Cloning, Molecular/methods , Cricetinae , DNA/metabolism , Embryonic and Fetal Development/physiology , Erythrocytes/enzymology , Glycopeptides/biosynthesis , Glycopeptides/isolation & purification , Humans , Molecular Sequence Data , N-Acetylglucosaminyltransferases/metabolism , Sequence Homology, Nucleic Acid , Transfection
13.
Immunology ; 64(1): 37-43, 1988 May.
Article in English | MEDLINE | ID: mdl-2454887

ABSTRACT

The Ina and Inb blood group antigens were found to be located on an erythrocyte membrane glycoprotein of 80,000 MW by immunoblotting with human anti-Ina and anti-Inb antibodies under non-reducing conditions. This glycoprotein is shown here to be identical to that defined by monoclonal antibodies to CDw44, and a new murine monoclonal antibody (BRIC 35) is added to this cluster. Experiments with endo-beta-galactosidase and Endo F preparations suggest that the glycoprotein contains one or more N-glycans but that these oligosaccharides do not contain extensive poly-N-acetyllactosaminyl sequences. Experiments using membranes prepared from sialidase-treated normal erythrocytes, from Tn erythrocytes and from Cad erythrocytes suggest that the glycoprotein does not contain a substantial content of O-glycans. The Inb antigen and the epitope defined by a murine monoclonal antibody (BRIC 35) show reduced expression on Lu(a-b-) erythrocytes which result from the effect of the dominant inhibitor gene In(Lu). Evidence is presented here that the Inb antigen is expressed on normal granulocytes and lymphocytes and on the haemopoietic cell lines HEL, K562 and HL-60, a lymphoblastoid cell line and lymphocytes from two patients with B-CLL.


Subject(s)
Blood Group Antigens/immunology , Erythrocyte Membrane/immunology , Glycoproteins/immunology , I Blood-Group System/immunology , Antibodies, Monoclonal/immunology , Cell Line , Electrophoresis, Polyacrylamide Gel , Epitopes/analysis , Genes, Dominant , Genes, MHC Class II , Humans , I Blood-Group System/genetics , Leukocytes/immunology , Molecular Weight , Receptors, Lymphocyte Homing
14.
Am J Hematol ; 25(3): 285-9, 1987 Jul.
Article in English | MEDLINE | ID: mdl-3037884

ABSTRACT

The finding of increased expression and apparently altered processing of Ii in hairy leukemic cells led us to test for Ii genomic alteration by Southern-type Ii cDNA hybridization to leukemic spleen DNA cleaved with a series of restriction endonucleases. Some insertions, deletions, or point mutations, potentially detectable by this technique, might correlate to alteration in expression and function of Ii (and indirectly, class II antigens). No changes in genomic structure of Ii were detected in DNA isolated from spleens of five patients with hairy cell leukemia, compared with DNA preparations from peripheral blood cells of nineteen healthy blood donors. These experiments were consistent with the view that gross structural alteration of the Ii genome had not occurred in hairy leukemic cells.


Subject(s)
Blood Group Antigens/genetics , DNA Restriction Enzymes/metabolism , I Blood-Group System/genetics , Leukemia, Hairy Cell/genetics , Collodion , DNA, Neoplasm/metabolism , Electrophoresis, Polyacrylamide Gel , Evaluation Studies as Topic , Genes , Humans , Leukemia, Hairy Cell/pathology , Nucleic Acid Hybridization , Paper
15.
Am J Clin Pathol ; 87(1): 101-2, 1987 Jan.
Article in English | MEDLINE | ID: mdl-3799539

ABSTRACT

The authors have identified a white patient with the red blood cell phenotype i, who also has congenital cataracts. However, in comparison with the strong association in Japanese patients between congenital cataracts and the i phenotype, the overall incidence of cataracts in white people with the i phenotype (three of ten people have congenital cataracts) is much lower. In addition, the authors studied the blood of 31 white patients with congenital cataracts and found no patients with the i phenotype. Thus, a close link between genes for these traits does not appear in most white patients with i red blood cell phenotypes.


Subject(s)
Blood Group Antigens/genetics , Cataract/congenital , I Blood-Group System/genetics , Adult , Cataract/genetics , Female , Humans , Pedigree , Phenotype
16.
Transfusion ; 26(1): 57-61, 1986.
Article in English | MEDLINE | ID: mdl-3946005

ABSTRACT

A 37-year-old white man who had never been transfused was admitted as an emergency patient with a ruptured spleen and a falling hematocrit (19% on admission). All crossmatches were incompatible. His serum contained anti-I, and his red cells (RBCs) were I-negative and strongly i-positive. Only 4 units of crossmatch-compatible I-negative frozen RBCs were available immediately. Because of the likelihood that more than 4 units would be required, chromium survival studies were performed using I-positive cells. Samples obtained at 15 and 30 minutes after injection revealed less than 1 percent survival of the donor RBCs. He received the 4 units of I-negative RBCs during the operation in addition to reinfusion of RBCs harvested from 1800 ml of blood aspirated from the abdominal cavity. The postoperative hematocrit remained greater than 30 percent and the bilirubin less than 1.5 mg per dl. Before recommending frozen storage of autologous RBCs, 51Cr labeled I-positive RBCs from the patient's daughter (obligate li heterozygote) were infused. Survival was 100 percent at 15 and 30 minutes, 90 percent at 3 hours, 85 percent at 26 hours; the remaining RBCs disappeared at a normal rate (T 1/2 27 days) over the succeeding 2 weeks. A repeat 51Cr-labeled RBC study with the original I-positive donor confirmed greater than 92 percent destruction in 90 minutes. The clinical significance of this allo-anti-l (apparently primarily against RBCs from homozygous I-positive donors) is in marked contrast to reported findings with auto-anti-l antibodies.


Subject(s)
Blood Group Antigens/immunology , Blood Group Incompatibility/blood , Hemorrhage/blood , I Blood-Group System/immunology , Isoantibodies/analysis , Adult , Anemia, Hemolytic, Autoimmune/blood , Blood Group Incompatibility/genetics , Chromatography, Ion Exchange , Chromium Radioisotopes , Complement Activation , Erythrocyte Aging , Erythrocyte Transfusion , Fetal Blood/immunology , Hemagglutination Tests , Humans , I Blood-Group System/genetics , Male
18.
Vox Sang ; 46(2): 75-9, 1984.
Article in English | MEDLINE | ID: mdl-6702145

ABSTRACT

The ABO group, Lewis type and secretor status were determined in 546 normal individuals (241 male, 305 female). Their serum was tested at 4 degrees C for agglutination of group O red blood cells; the antibody was presumed to be auto-anti-I; the results were expressed as a score. Among non-A female donors, the score was higher for secretors than nonsecretors (p less than 0.05). Among non-A secretors of both sexes, female donors had a higher score than male donors (p less than 0.05). These results suggest that the level of anti-I in the serum of normal individuals may be affected by the donor's ABO group, secretor status and sex.


Subject(s)
ABO Blood-Group System/genetics , Agglutinins/immunology , Saliva/immunology , Sex Characteristics , ABO Blood-Group System/immunology , Adolescent , Adult , Blood Grouping and Crossmatching , Cryoglobulins , Female , Hemagglutination Tests , Humans , I Blood-Group System/genetics , I Blood-Group System/immunology , Lewis Blood Group Antigens/genetics , Male
19.
Vox Sang ; 46(3): 157-60, 1984.
Article in English | MEDLINE | ID: mdl-6710968

ABSTRACT

The I-i- phenotype was found to be a familial character up to three generations in a large Indian family having 93 members. 15 members showed highly depressed Ii antigens while 6 of the members had partial depression of the Ii antigens on their red cells. It was evident in the family that the phenotype is associated with A1 antigen. The A1 antigen score on the red cells was significantly higher among the subjects with depressed Ii antigens. The I-i- status was not considered as a dominant or a recessive character nor does the partial depression of the Ii antigens indicate a heterozygous state of the variant gene.


Subject(s)
Blood Group Antigens/genetics , I Blood-Group System/genetics , ABO Blood-Group System/genetics , Female , Humans , India , Male , Pedigree , Phenotype , Suppression, Genetic
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