Alternative titles; symbols
HGNC Approved Gene Symbol: ART4
Cytogenetic location: 12p12.3 Genomic coordinates (GRCh38): 12:14,825,569-14,843,526 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.3 | [Blood group, Dombrock] | 616060 | 3 |
Mono-ADP-ribosylation is a posttranslational protein modification that involves the transfer of the ADP-ribose moiety from NAD+ to a specific amino acid in the target protein. This modification helps regulate cellular metabolism in prokaryotes and is the mechanism by which some bacterial toxins function. The rodent T-cell alloantigen Rt6 has structural homology to prokaryotic ADP-ribosylation proteins and possesses mono-ADP-ribosyltransferase enzyme activity. By searching an EST database with the deduced protein sequences of ART1 (601625) and ART2P (see ART1), both of which are homologous to Rt6, Koch-Nolte et al. (1997) identified human cDNAs encoding ART3 (603086) and ART4. They isolated the corresponding genes from P1 and PAC1 genomic clones by PCR using EST-derived primers. Southern blot analysis demonstrated that human ART4 is a single-copy gene which has homologs in other primates and in mouse. Northern blot analysis detected prominent ART4 transcripts of 1.4, 2.4, and 5.5 kb only in spleen, or T-cell, RNA. The predicted ART3 and ART4 proteins contain structural motifs similar to those in ADP-ribosylating toxins, as well as hydrophobic N-terminal and C-terminal signal peptides characteristic of glycosylphosphatidylinositol (GPI)-anchored cell membrane proteins; unlike ART3, ART4 does not contain a repeated motif at the C terminus. Koch-Nolte et al. (1997) reported that ART1 is the closest known family member of ART4, with 39% amino acid sequence identity.
Gubin et al. (2000) provided the first molecular description of the Dombrock (Do) blood group system (616060). A candidate gene, ART4, which they called DOK1, was identified by in silico analyses of approximately 5,000 ESTs from terminally differentiating human erythroid cells. Transfection experiments demonstrated specific binding of anti-Dombrock and confirmed GPI membrane attachment. DOK1 expression was developmentally regulated during erythroid differentiation and occurred at highest levels in fetal liver. Homology studies suggested that DOK1 is a member of the ADP-ribosyltransferase ectoenzyme gene family.
Lucien et al. (2002) noted that the ART4 gene encodes a predicted 314-amino acid polypeptide containing an arginine-glycine-aspartic acid (RGD) motif, present in the DO*B allele product only, that is commonly involved in cell-cell interactions involving integrin binding and the GPI anchor motif. They stated that although the identity of DO to ART4 had been established, enzymatic activity had not been demonstrated in any cell type, including erythroid cells.
A comparison of the genomic and cDNA sequences of ART4 by Koch-Nolte et al. (1997) revealed a conserved exon/intron structure, with an unusually large exon encoding the mature protein.
The ART4 gene contains 3 exons spanning 14 kb (Gubin et al., 2000).
By PCR screening of human/rodent somatic cell hybrids and by in situ hybridization, Koch-Nolte et al. (1997) mapped the ART4 gene to 12p13.1-p12.2.
Gross (2014) mapped the ART4 gene to chromosome 12p12.3 based on an alignment of the ART4 sequence (GenBank AF290204) with the genomic sequence (GRCh38).
Genotypic comparisons performed by Gubin et al. (2000) suggested that Do(a) versus Do(b) antigenicity of the Do blood group system results from a single amino acid substitution within an encoded RGD motif of ART4 (110600.0001).
The antithetical Dombrock antigens Do(a)/Do(b) also carry 3 high-incidence antigens: Gregory (Gy(a)), Holley (Hy), and Joseph (Jo(a)) (Lucien et al., 2002). The Hy polymorphisms derive from a DO*B background. The rare Dombrock-null phenotype, in which the RBCs lack all 5 antigens, may arise from a single nucleotide mutation in the acceptor splice site of intron 1, causing the skipping of exon 2 (110600.0002) (Rios et al., 2001) or from the absence of GPI-anchored proteins on RBCs from patients with paroxysmal nocturnal hemoglobinemia (PNH; 300818).
Rios et al. (2002) studied 2 probands in whom RBCs with the Dombrock-null phenotype lacked all antigens in the Dombrock blood group system. Sequence analysis of DNA from 1 proband with the Dombrock-null phenotype revealed a T-to-C mutation (110600.0004) with outsplicing of exon 2. The second proband was homozygous for a 442C-T mutation (110600.0005) in exon 2.
Lucien et al. (2002) identified an 8-bp deletion (110600.0003) in the ART4 gene in a woman with the DO-null phenotype.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
To determine if ART4 polymorphisms correlate with Do blood group (616060) antigenicity, Gubin et al. (2000) studied 8 blood donors of defined serology, i.e., 4 Do(a+b-) and 4 Do(a-b+), and sequenced the coding region of ART4. Three SNP sites were identified. While 2 SNPs did not alter the predicted amino acid primary structure, the third predicted a change in the protein sequence, asn265 to asp (N265D). This SNP fell within an RGD adhesion motif of the molecule. All 3 SNP sites were consistent among the 8 donors, with N265 found in the 4 Do(a+b-) samples, and D265 found the 4 Do(a-b+) samples.
Rios et al. (2001) identified an A-to-G mutation in the 3-prime splice site of intron 1 of the ART4 gene in 3 probands with the Dombrock-null phenotype (616060).
Lucien et al. (2002) identified a novel alteration of the DO*A allele of the Dombrock blood group system (616060) in a female DO-null donor from Reunion Island with allo-anti-DO3 in her serum; her parents were consanguineous. The only deviation from the wildtype DO*A allele sequence was an 8-bp (nucleotides 343-350) deletion within exon 2. This short deletion generated a premature stop codon and encoded a truncated protein lacking the predicted functional motif of the ADP-ribosyltransferase enzyme and the glycosylphosphatidylinositol anchor motif essential for RBC membrane attachment. An allele-specific PCR to detect the DO(del8) deletion was developed.
Rios et al. (2002) described the Dombrock-null phenotype (616060) in a proband with a T-to-C substitution in the donor splice site of the ART4 gene, resulting in outsplicing of exon 2.
In a proband with the Dombrock-null phenotype (616060), Rios et al. (2002) found homozygosity for a 442C-T mutation in exon 2 of the ART4 gene, resulting in a premature stop codon, gln148 to ter (Q148X).
Gross, M. B. Personal Communication. Baltimore, Md. 10/23/2014.
Gubin, A. N., Njoroge, J. M., Wojda, U., Pack, S. D., Rios, M., Reid, M. E., Miller, J. L. Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family. Blood 96: 2621-2627, 2000. [PubMed: 11001920]
Koch-Nolte, F., Haag, F., Braren, R., Kuhl, M., Hoovers, J., Balasubramanian, S., Bazan, F., Thiele, H.-G. Two novel human members of an emerging mammalian gene family related to mono-ADP-ribosylating bacterial toxins. Genomics 39: 370-376, 1997. Note: Erratum: Genomics 55: 130 only, 1999. [PubMed: 9119374] [Full Text: https://doi.org/10.1006/geno.1996.4520]
Lucien, N., Celton, J.-L., Le Pennec, P.-Y., Cartron, J.-P., Bailly, P. Short deletion within the blood group Dombrock locus causing a Do(null) phenotype. Blood 100: 1063-1064, 2002. [PubMed: 12130524] [Full Text: https://doi.org/10.1182/blood-2001-12-0298]
Rios, M., Hue-Roye, K., Lee, A. H., Chiofolo, J. T., Miller, J. L., Reid, M. E. DNA analysis for the Dombrock polymorphism. Transfusion 41: 1143-1146, 2001. [PubMed: 11552072] [Full Text: https://doi.org/10.1046/j.1537-2995.2001.41091143.x]
Rios, M., Hue-Roye, K., Storry, J. R., Lee, T., Miller, J. L., Reid, M. E. Molecular basis of the Dombrock null phenotype. Transfusion 41: 1405-1407, 2001. [PubMed: 11724986] [Full Text: https://doi.org/10.1046/j.1537-2995.2001.41111405.x]
Rios, M., Storry, J. R., Hue-Roye, K., Chung, A., Reid, M. E. Two new molecular bases for the Dombrock null phenotype. Brit. J. Haemat. 117: 765-767, 2002. [PubMed: 12028057] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03524.x]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.