Insulin-dependent (type I) diabetes mellitus (IDDM) is a genetic heterogenous autoimmune disorder, which is triggered by genetic predisposition and environmental factors.Davies, J.L., et al., A genome-wide search for human type 1 diabetes susceptibility genes. Nature, 1994. 371(6493): p. 130-136. The prevalence of insulin-dependent (type I) diabetes mellitus (IDDM) among children and young adult from Europe is approximately 0.4%.Zollo, M., P. Dear, and F. Pociot, Insulin‐dependent Diabetes Mellitus (IDDM): Identifying the Disease‐causing Gene at the IDDM11 Locus. eLS. Insulin-dependent (type I) diabetes mellitus (IDDM) is characterized by acute onset and insulin deficiency.Harjutsalo, V., Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland. 2007. Patients with insulin-dependent (type I) diabetes mellitus (IDDM) are found with gradual loss of the pancreatic islet beta cells and therefore not able to produce insulin. As a result, they usually need exogenous insulin to maintain their life.
Gene location of IDDM Genome-wide linkage analysis could be used for identification in susceptibility genes of insulin-dependent (type I) diabetes mellitus (IDDM).Pociot, F. and M. McDermott, Genetics of type 1 diabetes mellitus. Genes and immunity, 2002. 3(5): p. 235-249. This analysis verifies that eighteen different genome regions are predisposed to insulin-dependent (type I) diabetes mellitus(IDDM). There are 18 different symbols of genome region, which is labeled from IDDM1 to IDDM18. The MHC HLA gene (IDDM1) and the insulin gene INS (IDDM2) are the major genetic candidates in the development of insulin-dependent (type I) diabetes mellitus(IDDM), which are located on the chromosome 6p21.3 and chromosome 11p15 respectively. IDDM3, IDDM4, IDDM5 IDDM7 reside in chromosome 15q26, chromosome 11q13, chromosome 6q25 and 2q31 respectively.Field, L.L., et al., Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24. 3–q31. Genomics, 1996. 33(1): p. 1-8.IDDM11 (insulin-dependent diabetes mellitus 11) is one of the susceptibility genes for IDDM which locates on chromosome 14q24.3-q31.Kayashima, T., et al., Maternal isodisomy for 14q21‐q24 in a man with diabetes mellitus. American journal of medical genetics, 2002. 111(1): p. 38-42. This loci is identified by linkage to D14S67 marker via a sibling-pair linkage analysis Based on the previous study, the biological behavior of IDDM11is different to HLA region genes so that IDDM11 is less predisposing to HLA. Moreover, IDDM11 has more involvement on the families that are less predisposing to HLA, while IDDM11 has less involvement on the families that are more predisposing to HLA. The rest of susceptibility genes locus in insulin-dependent (type I) diabetes mellitus (IDDM)are shown in table 1. LocusChrosome Candidate gene/ Microsatellites IDDM1 6p21 HLA-DR/ DQ IDDM2 11p15.5 INS-VNTRIDDM3 15q26 D15S107IDDM4 11q13 MDU1, ZFM1, RT6, FADD, LRP5 IDDM5 6q25 ESR, MnSOD IDDM6 18q12-q21 D18S487, D18S64, JK (Kidd locus)IDDM7 2q31 D2S152, IL-1, NEUROD, GALNT3, HOXD8IDDM8 6q25-27 D6S264, D6S446, D6S281 IDDM9 3q21-25D3S1303, D3S1589, D3S3606 IDDM10 10p11-q11 D10S193, D10S208, D10S588, D10S1426IDDM11 14q24.3-q31 D14S67 IDDM12 2q33 CTLA-4, CD28 IDDM13 2q34 D2S137, D2S164, IGFBP2, IGFBP5 IDDM14 2q34-q35 NCBI # 3413 IDDM15 6q21 D6S283, D6S434, D6S1580 IDDM16 14q32 IGH IDDM17 10q25 D10S1750-D10S1773 IDDM18 5q31.1-33.1 IL12B Table 1 The locus for susceptibility genes for IDDM.
Gene characteristics of IDDM Most regions of IDDM loci are 1 to 40 cM, which are corresponded to 1 to 40Mb. Each region of IDDM consists several genes.
Mutations The etiological mutations of all IDDM loci have not been found.
Controversies
SEL1L gene (sel-1 suppressor of Lin-12-like Caenorhabdits elegans) is a negative regulator of the Notch signaling pathway that is responsible for pancreatic endocrine cell development.Pociot, F., et al., No evidence for SEL1L as a candidate gene for IDDM11‐conferred susceptibility. Diabetes/metabolism research and reviews, 2001. 17(4): p. 292-295. SEL1L gene is located on chromosome 14q24.3-31. The locus of SEL1L is near to D14S67 marker used for identification of IDDM 11 so that SEL1L gene can serve as a candidate gene for IDDM11. However, the present researchers are object to this thesis. The present researchers use LD (Linkage disequilibrium) analyses and TDT (transmission disequilibrium test) to analyze the SEL1L gene among Danish and Sardinian families. The research result indicates that the SEL1L gene is not supposed to a candidate gene for IDDM11. In addition, other candidate genes for IDDM11 could be tested and identified by using single nucleotide polymorphism (SNP) technology. The following table shows some candidate genes for IDDM11. Gene ENSA (endosulfine alpha) RGS6 (regulator of G-protein signaling 6) CHES1 (checkpoint suppressor 1) ESRRB (estrogen-related receptor beta) KCNK2 (potassium channel, subfamily K, member 2) MAP3K9 (mitogen-activated protein kinase 9) CALM1 (calmodulin 1 phosphorylase kinase, delta) NUMB (numb homolog Drosophila) Table 2 Candidate genes for IDDM11.
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