Alternative titles; symbols
DO: 0110744;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q25.1 | {Diabetes mellitus, insulin-dependent, 5} | 600320 | 3 | SUMO4 | 608829 |
A number sign (#) is used with this entry because of evidence that susceptibility to type 1 diabetes-5 (T1D5) is conferred by variation in the SUMO4 gene (608829) on chromosome 6q25.
For a general phenotypic description of type 1 diabetes mellitus, see T1D (222100).
In a screen of the human genome for type 1 diabetes susceptibility genes, Davies et al. (1994) assigned one such locus, designated IDDM5, to 6q24-q27. This assignment was confirmed in additional datasets of sib-pair families. Luo et al. (1996) confirmed linkage for IDDM5 and narrowed the locus to a 5-cM genomic interval on 6q25.
Genome scans of families with insulin-dependent diabetes mellitus suggested that multiple loci make incremental contributions to disease susceptibility (see Concannon et al., 1998). Analysis of IDDM in humans has been aided by studies of the nonobese diabetic (NOD) mouse model, which closely resembles the human disease. Using the NOD model, Fox et al. (2000) identified an early step in diabetes pathogenesis that behaves as a highly penetrant trait. They reported that NOD-derived alleles at both the Idd5 and Idd13 (IDDM13; 601318) loci regulate a T lymphocyte-dependent progression from a benign to a destructive stage of insulitis. Human chromosomal regions orthologous to the Idd5 and Idd13 intervals are also linked to diabetes risk, suggesting that conserved genes encoded at these loci are central regulators of disease pathogenesis. Fox et al. (2000) claimed that these data were the first to reveal a role for individual non-MHC Idd loci in a specific, critical step in diabetes pathogenesis, namely, T-cell recruitment to islet lesions driving destructive inflammation. The study illustrated the usefulness of identifying intermediate phenotypes in complex disease pathogenesis as an approach to gene identification.
Guo et al. (2004) presented evidence for an association between type 1 diabetes mellitus and multiple single-nucleotide polymorphisms (SNPs) in 197 kb of genomic DNA in the IDDM5 interval. They cloned the SUMO4 gene, encoding small ubiquitin-like modifier-4 protein, in the interval. A missense substitution (M55V; 608829.0001) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with type 1 diabetes. Bohren et al. (2004) demonstrated association of the M55V polymorphism of SUMO4 with type 1 diabetes susceptibility in families.
Bohren, K. M., Nadkarni, V., Song, J. H., Gabbay, K. H., Owerbach, D. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J. Biol. Chem. 279: 27233-27238, 2004. [PubMed: 15123604] [Full Text: https://doi.org/10.1074/jbc.M402273200]
Concannon, P., Gogolin-Ewens, K. J., Hinds, D. A., Wapelhorst, B., Morrison, V. A., Stirling, B., Mitra, M., Farmer, J., Williams, S. R., Cox, N. J., Bell, G. I., Risch, N., Spielman, R. S. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 19: 292-296, 1998. [PubMed: 9662408] [Full Text: https://doi.org/10.1038/985]
Davies, J. L., Kawaguchi, Y., Bennett, S. T., Copeman, J. B., Cordell, H. J., Pritchard, L. E., Reed, P. W., Gough, S. C. L., Jenkins, S. C., Palmer, S. M., Balfour, K. M., Rowe, B. R., Farrall, M., Barnett, A. H., Bain, S. C., Todd, J. A. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371: 130-136, 1994. [PubMed: 8072542] [Full Text: https://doi.org/10.1038/371130a0]
Fox, C. J., Paterson, A. D., Mortin-Toth, S. M., Danska, J. S. Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. Am. J. Hum. Genet. 67: 67-81, 2000. [PubMed: 10848492] [Full Text: https://doi.org/10.1086/302995]
Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., Zheng, W., Purohit, S., Podolsky, R. H., Muir, A., Wang, J., Dong, Z., and 15 others. A functional variant of SUMO4, a new I-kappa-B-alpha modifier, is associated with type 1 diabetes. Nature Genet. 36: 837-841, 2004. Note: Erratum: Nature Genet. 36: 1024 only, 2004. [PubMed: 15247916] [Full Text: https://doi.org/10.1038/ng1391]
Luo, D. F., Buzzetti, R., Rotter, J. I., Maclaren, N. K., Raffel, L. J., Nistico, L., Giovannini, C., Pozzilli, P., Thomson, G., She, J. X. Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8. Hum. Molec. Genet. 5: 693-698, 1996. [PubMed: 8733139] [Full Text: https://doi.org/10.1093/hmg/5.5.693]