Alternative titles; symbols
HGNC Approved Gene Symbol: GCNT2
SNOMEDCT: 115752000;
Cytogenetic location: 6p24.3-p24.2 Genomic coordinates (GRCh38): 6:10,521,351-10,629,368 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p24.3-p24.2 | [Blood group, Ii] | 110800 | Autosomal dominant | 3 |
| Adult i phenotype without cataract | 110800 | Autosomal dominant | 3 | |
| Cataract 13 with adult i phenotype | 116700 | Autosomal recessive | 3 |
The blood group i/I antigens (110800) 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 the result of the appearance of a beta-1,6-N-acetylglucosaminyltransferase, the I-branching enzyme (GCNT2). Bierhuizen et al. (1993) cloned the cDNA for the branching enzyme that converts the linear form into the branched form and studied its expression with development of I antigen in transfected cells. The cDNA sequence predicted a protein of type II membrane topology as has been found for all other mammalian glycosyltransferases. 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 (GCNT1; 600391) are strongly homologous in the center of their putative catalytic domains.
Yu et al. (2003) demonstrated that the human I locus expresses 3 IGNT forms, designated IGNTA, IGNTB, and IGNTC, which have different exons 1, but identical exons 2 and 3. IGNTC is the only one of the 3 IGNT transcripts expressed in reticulocytes, whereas only the IGNTB transcript is expressed in lens epithelium cells.
In the course of mapping 39 ESTs to 6p24-p23, Olavesen et al. (1997) concluded that the GCNT2 gene is located in the region between EDN1 (131240) at 6p24-p23 on the centromeric side and TFAP2 (107580) at 6p24 on the telomeric side.
The null phenotype of blood group I, the adult i phenotype (110800), results from a defect in the specific transferase that converts the structure of the antigen from linear to branched repeats of N-acetyllactosamine, which characterize blood group antigen i and I, respectively.
The adult i phenotype was found to be associated with congenital cataract (CTRCT13; 116700) in Japanese (Ogata et al., 1979) and Taiwanese (Lin-Chu et al., 1991). Yu et al. (2001) identified molecular defects in the GCNT2 gene in 3 Taiwanese families with adult i blood group phenotype and congenital cataracts (600429.0001-600429.0003).
Yu et al. (2003) performed molecular genetic analyses of the 2 groups of adult i, those with and those without congenital cataracts, and performed enzyme function assays and expression patterns for the 3 IGNT transcripts in reticulocytes and lens epithelium cells. The results suggested a molecular genetic mechanism that may explain the partial association of the adult i phenotype with congenital cataracts and indicated that a defect in the I locus may lead directly to the development of congenital cataracts. The results also suggested that the human blood group I gene should be reassigned to the IGNTC form rather than the IGNTB form. Of the 3 IGNT forms, Yu et al. (2003) found that IGNTA and IGNTB were wildtype, but IGNTC was mutant, in adult i white individuals without congenital cataracts. Two missense mutations of IGNTC, ala169 to thr (600429.0004) and arg228 to gln (600429.0005), were identified in adult i whites without congenital cataracts. Five of 6 whites were homozygous for the thr169 allele and 1 was compound heterozygous for the thr169 and gln228 missense changes. These mutations were found to be uncommon in the general white population. Whereas only IGNTC was mutant in adult i whites without congenital cataracts, all 3 IGNT forms were mutated in the adult i Taiwanese individuals with congenital cataracts. IGNTC is the only one of the 3 IGNT transcripts expressed in reticulocytes, whereas only the IGNTB transcript is expressed in lens epithelium cells.
Marsh and Depalma (1982) noted that the association of the adult i phenotype with congenital cataract might be explained either by close linkage between independent I- and cataract-related genes or by a pleiotropic effect of the gene responsible for the adult i phenotype on the development of cataracts. Because of the reduced 'strength' of the association in whites, it had been suggested that the former hypothesis of close linkage between 2 independent genes was the more tenable one. Molecular factors suggested that the association may result from a pleiotropic effect of the same gene mutation and not from a linkage of 2 independent genes, because it was unlikely that 2 nucleotide changes in the I gene would be linked to the nearby gene that had, by chance, also mutated to result in the development of cataracts.
In 2 Taiwanese families with cataract and the adult i phenotype (CTRCT13; 116700), Yu et al. (2001) identified mutations in the GCNT2 gene. Affected members of pedigree S had a homozygous 1043G-A transition resulting in a gly348-to-glu (G348E) substitution. Affected members of pedigree W were compound heterozygous for the G348E mutation and a 1148G-A transition resulting in an arg383-to-his (R383H; 600429.0002) substitution. The parents were heterozygous for one or the other of the mutations and neither family was consanguineous. Both mutations abolished the original enzyme activity.
For discussion of the arg383-to-his (R383H) mutation in the GCNT2 gene that was found in compound heterozygous state in patients with cataract and the adult i phenotype (CTRCT13; 116700) by Yu et al. (2001), see 600429.0001.
In a Taiwanese family (pedigree C), Yu et al. (2001) found that a member with congenital cataract and the adult i phenotype (CTRCT13; 116700) was homozygous for deletion of all 3 exons of the GCNT2 gene. The parents were first cousins.
In 5 of 6 whites with the adult i phenotype (see 110800), Yu et al. (2003) found homozygosity for a 505G-A mutation in 1 of the isoforms expressed from the GCNT2 gene, IGNTC. This predicted the amino acid change ala169 to thr (A169T). Yu et al. (2003) suggested that no cataract is associated with this mutation because only the IGNTB transcript is expressed in lens-epithelium cells.
In 1 of 6 whites with the adult i phenotype (see 110800), Yu et al. (2003) found compound heterozygosity for mutations in the IGNTC isoform of GNTC2: ala169-to-thr (600429.0004) and a 683G-A transition, predicted to result in an arg228-to-gln (R228Q) substitution. Yu et al. (2003) suggested that no cataract is associated with this mutation because only the IGNTB transcript is expressed in lens-epithelium cells.
Bierhuizen, M. F. A., Mattei, M.-G., Fukuda, M. Expression of the developmental I antigen by a cloned human cDNA encoding a member of a beta-1,6-N-acetylglucosaminyltransferase gene family. Genes Dev. 7: 468-478, 1993. [PubMed: 8449405] [Full Text: https://doi.org/10.1101/gad.7.3.468]
Lin-Chu, M., Broadberry, R. E., Okubo, Y., Tanaka, M. The i phenotype and congenital cataracts among Chinese in Taiwan (Letter) Transfusion 31: 676-677, 1991. [PubMed: 1891797] [Full Text: https://doi.org/10.1046/j.1537-2995.1991.31791368349.x]
Marsh, W. L., DePalma, H. Association between the Ii blood group and congenital cataract. Transfusion 22: 337-338, 1982. [PubMed: 7101428] [Full Text: https://doi.org/10.1046/j.1537-2995.1982.22482251224.x]
Ogata, H., Okubo, Y., Akabane, T. Phenotype i associated with congenital cataract in Japanese. Transfusion 19: 166-168, 1979. [PubMed: 432928] [Full Text: https://doi.org/10.1046/j.1537-2995.1979.19279160286.x]
Olavesen, M. G., Bentley, E., Mason, R. V. F., Stephens, R. J., Ragoussis, J. Fine mapping of 39 ESTs on human chromosome 6p23-p25. Genomics 46: 303-306, 1997. [PubMed: 9417921] [Full Text: https://doi.org/10.1006/geno.1997.5032]
Schwientek, T., Nomoto, M., Levery, S. B., Merkx, G., Geurts van Kessel, A., Bennett, E. P., Hollingsworth, M. A., Clausen, H. Control of O-glycan branch formation: molecular cloning of human cDNA encoding a novel beta-1,6-N-acetylglucosaminyltransferase forming core 2 and core 4. J. Biol. Chem. 274: 4504-4512, 1999. [PubMed: 9988682] [Full Text: https://doi.org/10.1074/jbc.274.8.4504]
Yeh, J.-C., Ong, E., Fukuda, M. Molecular cloning and expression of a novel beta-1,6-N-acetylglucosaminyltransferase that forms core 2, core 4, and I branches. J. Biol. Chem. 274: 3215-3221, 1999. [PubMed: 9915862] [Full Text: https://doi.org/10.1074/jbc.274.5.3215]
Yu, L.-C., Twu, Y.-C., Chang, C.-Y., Lin, M. Molecular basis of the adult i phenotype and the gene responsible for the expression of the human blood group I antigen. Blood 98: 3840-3845, 2001. [PubMed: 11739194] [Full Text: https://doi.org/10.1182/blood.v98.13.3840]
Yu, L.-C., Twu, Y.-C., Chou, M.-L., Reid, M. E., Gray, A. R., Moulds, J. M., Chang, C.-Y., Lin, M. The molecular genetics of the human I locus and molecular background explain the partial association of the adult i phenotype with congenital cataracts. Blood 101: 2081-2088, 2003. [PubMed: 12424189] [Full Text: https://doi.org/10.1182/blood-2002-09-2693]