A novel I-branching β-1,6-N-acetylglucosaminyltransferase involved in human blood group I antigen expression

Abstract

The human blood group i and I antigens are determined by linear and branched poly-N-acetyllactosamine structures, respectively. In erythrocytes, the fetal i antigen is converted to the adult I antigen by I-branching ␤-1,6-N-acetylglucosaminyltransferase (IGnT) during development. Dysfunction of the I-branching enzyme may result in the adult i phenotype in erythrocytes. However, the I gene responsible for blood group I antigen has not been fully confirmed. We report here a novel human I-branching enzyme, designated IGnT3. The genes for IGnT1 (reported in 1993), IGnT2 (also presented in this study), and IGnT3 consist of 3 exons and share the second and third exons. Bone marrow cells preferentially expressed IGnT3 transcript. During erythroid differentiation using CD34 ؉ cells, IGnT3 was markedly up-regulated with concomitant decrease in IGnT1/2. Moreover, reticulocytes expressed the IGnT3 transcript, but IGnT1/2 was below detectable levels. By molecular genetic analyses of an adult i pedigree, individuals with the adult i phenotype were revealed to have heterozygous alleles with mutations in exon 2 (1006G>A; Gly336Arg) and exon 3 (1049G>A; Gly350Glu), respectively, of the IGnT3 gene. Chinese hamster ovary (CHO) cells transfected with each mutated IGnT3 cDNA failed to express I antigen. These findings indicate that the expression of the blood group I antigen in erythrocytes is determined by a novel IGnT3, not by IGnT1 or IGnT2.

Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes

“…Recessive mutations (seven in total) in GCNT2, which encodes glucosaminyl (N-acetyl) transferase 2, have been reported in Japanese, Taiwanese, Arab, and Pakistani families with congenital cataract and adult I blood group and encompass missense, nonsense, and genomic alterations. [10][11][12][13] The missense mutation we report in this study (c.1040A>G; p.Tyr347Cys), which fully segregated with the phenotype in the family, is predicted to be pathogenic by in silico analysis and is very well conserved down to acorn worm and Xenopus. In addition, it is absent in 192 Saudi controls by Sanger sequencing and 160 Saudi controls by exome sequencing.…”

IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts

“…In addition to the globin genes, the human fetal-to-adult developmental transition is characterized by increased expression of the carbonic anhydrase I (CA1) gene and carbohydrate modification due to the increased expression of the GCNT2 gene (17)(18)(19)(20). Interestingly, both CA1 and GCNT2 were significantly downregulated in IGF2BP1-OE cells compared with empty vector control transductions (Fig.…”

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia

“…Rare individuals do not branch their i-antigen due to inheritance of an autosomal recessive mutation in the transferase gene. 16,17 In a library of 30 VH4-34 encoded antibodies, mAb216 was found to have high binding and cytotoxicity against normal B lymphocytes, B-cell lymphomas and B-progenitor lymphoblasts. [18][19][20] Binding of mAb216 to its linear lactosamine ligand leads to disruption of the plasma membrane and formation of large membrane pores resulting in cell lysis (Online Supplementary Figure S1).…”