IDDM11

Last updated April 08, 2019

Insulin-dependent (type I)diabetes mellitus (IDDM) is a genetic heterogenouse autoimmune disorder, which is triggered by genetic predisposition and environmental factors.^[1] The prevalence of insulin-dependent (type I) diabetes mellitus (IDDM) among children and young adult from Europe is approximately 0.4%.^[2] Insulin-dependent (type I) diabetes mellitus (IDDM) is characterized by acute onset and insulin deficiency.^[2]^[3] 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.^[2]^[3] As a result, they usually need exogenous insulin to maintain their life.^[2]^[3]

Diabetes mellitus type 1, also known as type 1 diabetes, is a form of diabetes mellitus in which very little or no insulin is produced by the pancreas. Before treatment this results in high blood sugar levels in the body. The classic symptoms are frequent urination, increased thirst, increased hunger, and weight loss. Additional symptoms may include blurry vision, feeling tired, and poor wound healing. Symptoms typically develop over a short period of time.

Beta cells are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with type I or type II diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.

Insulin is a protein hormone that is used as a medication to treat high blood glucose. This includes in diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. It is also used along with glucose to treat high blood potassium levels. Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle.

Gene location of IDDM

Genome-wide linkage analysis could be used for identification in susceptibility genes of insulin-dependent (type I) diabetes mellitus (IDDM).^[4] 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.^[3] 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.^[1]^[4] IDDM3, IDDM4, IDDM5 IDDM7 reside in chromosome 15q26, chromosome 11q13, chromosome 6q25 and 2q31 respectively.^[5]IDDM11 (insulin-dependent diabetes mellitus 11) is one of the susceptibility genes for IDDM which locates on chromosome 14q24.3-q31.^[2]^[6] This loci is identified by linkage to D14S67 marker via a sibling-pair linkage analysis^[2]^[6] Based on the previous study, the biological behavior of IDDM11is different to HLA region genes so that IDDM11 is less predisposing to HLA.^[5] 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.^[5]

HLA-DQB1 protein-coding gene in the species Homo sapiens

Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene. The protein encoded by this gene is one of two proteins that are required to form the DQ heterodimer, a cell surface receptor essential to the function of the immune system.

The rest of susceptibility genes locus in insulin-dependent (type I) diabetes mellitus (IDDM)are shown in table 1.^[3]

Locus	Chrosome	Candidate gene/ Microsatellites
IDDM1	6p21	HLA-DR/ DQ
IDDM2	11p15.5	INS-VNTR
IDDM3	15q26	D15S107
IDDM4	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, HOXD8
IDDM8	6q25-27	D6S264, D6S446, D6S281
IDDM9	3q21-25	D3S1303, D3S1589, D3S3606
IDDM10	10p11-q11	D10S193, D10S208, D10S588, D10S1426
IDDM11	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.^[2]

In genetics, a centimorgan or map unit (m.u.) is a unit for measuring genetic linkage. It is defined as the distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. It is often used to infer distance along a chromosome. However, it is not a true physical distance.

Genome size is the total amount of DNA contained within one copy of a single genome. It is typically measured in terms of mass in picograms or less frequently in Daltons or as the total number of nucleotide base pairs typically in megabases. One picogram equals 978 megabases. In diploid organisms, genome size is used interchangeably with the term C-value. An organism's complexity is not directly proportional to its genome size; some single cell organisms have much more DNA than humans.

Mutations

The etiological mutations of all IDDM loci have not been found.^[2]

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.^[2]^[7] SEL1L gene is located on chromosome 14q24.3-31.^[2]^[7] 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.^[2]^[7] 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.^[2] The research result indicates that the SEL1L gene is not supposed to a candidate gene for IDDM11.^[2] 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.^[2]

Notch signaling pathway A series of molecular signals initiated by the binding of an extracellular ligand to the receptor Notch on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription.

The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

In population genetics, linkage disequilibrium is the non-random association of alleles at different loci in a given population. Loci are said to be in linkage disequilibrium when the frequency of association of their different alleles is higher or lower than what would be expected if the loci were independent and associated randomly.

The transmission disequilibrium test (TDT) was proposed by Spielman, McGinnis and Ewens (1993) as a family-based association test for the presence of genetic linkage between a genetic marker and a trait. It is an application of McNemar's test.

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.

Related Research Articles

ENU, also known as N-ethyl-N-nitrosourea (chemical formula C₃H₇N₃O₂), is a highly potent mutagen. For a given gene in mice, ENU can induce 1 new mutation in every 700 loci. It is also toxic at high doses.

Takayasu's arteritis is a form of large vessel granulomatous vasculitis with massive intimal fibrosis and vascular narrowing, most commonly affecting often young or middle-age women of Asian descent, though anyone can be affected. It mainly affects the aorta and its branches, as well as the pulmonary arteries. Females are about 8–9 times more likely to be affected than males.

Genetic association is when one or more genotypes within a population co-occur with a phenotypic trait more often than would be expected by chance occurrence.

Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells. It contains the Major Histocompatibility Complex, which contains over 100 genes related to the immune response, and plays a vital role in organ transplantation.

Non-obese diabetic or NOD mice, like the Biobreeding rat, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. Onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycemia. It is recommended to monitor for development of glycosuria from 10 weeks of age; this can be carried out using urine glucose dipsticks. NOD mice will develop spontaneous diabetes when left in a sterile environment. The incidence of spontaneous diabetes in the NOD mouse is 60-80% in females and 20-30% in males. Onset of diabetes also varies between males and females: commonly, onset is delayed in males by several weeks.

HLA-DQ9 (DQ9) is a human leukocyte antigen serotype within the HLA-DQ (DQ) serotype group. DQ9 is a split antigen of the DQ3 broad antigen. DQ9 is determined by the antibody recognition of β⁹ and this generally detects the gene product of DQB1*0303.

Calpain-10 is a protein that in humans is encoded by the CAPN10 gene.

Small ubiquitin-related modifier 4 is a protein that in humans is encoded by the SUMO4 gene.

Large proline-rich protein BAT2 is a protein that in humans is encoded by the BAT2 gene.

Receptor-type tyrosine-protein phosphatase N2 (R-PTP-N2) also known as islet cell autoantigen-related protein (ICAAR) and phogrin is an enzyme that in humans is encoded by the PTPRN2 gene. PTPRN and PTPRN2 are both found to be major autoantigens associated with insulin-dependent diabetes mellitus.

Forkhead box protein N3 is a protein that in humans is encoded by the FOXN3 gene.

Complement C4-A is a protein that in humans is encoded by the C4A gene.

HLA A1-B8 is a multigene haplotype that covers the MHC Class I region of the human major histocompatibility complex on chromosome 6. A multigene haplotype is set of inherited alleles covering several genes, or gene-alleles; common multigene haplotypes are generally the result of identity by descent from a common ancestor. Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations.

MODY 6 is a form of maturity onset diabetes of the young.

The Haplotype-relative-risk (HRR) method is a family-based method for determining gene allele association to a disease in the presence of actual genetic linkage. Nuclear families with one affected child are sampled using the parental haplotypes not transmitted as a control. While similar to the genotype relative risk (RR), the HRR provides a solution to the problem of population stratification by only sampling within family trios. The HRR method was first proposed by Rubinstein in 1981 then detailed in 1987 by Rubinstein and Falk and is an important tool in genetic association studies.

Most cases of diabetes mellitus type 2 involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.

At least 20 different chromosomal regions have been linked to type 1 diabetes (T1D) susceptibility in humans, using genome screening, candidate gene testing, and studies of human homologues of mouse susceptibility genes.

GWAS in allergy is a study of a meta-analysis of GWAS in which allergy is associated with different susceptibility loci. The three allergic phenotypes studied were to cat, dust mites and pollen, for which found patients presenting allergic symptoms.

References

1 2 Davies, J.L., et al., A genome-wide search for human type 1 diabetes susceptibility genes. Nature, 1994. 371(6493): p. 130-136.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Zollo, M., P. Dear, and F. Pociot, Insulin‐dependent Diabetes Mellitus (IDDM): Identifying the Disease‐causing Gene at the IDDM11 Locus. eLS.
1 2 3 4 5 Harjutsalo, V., Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland. 2007.
1 2 Pociot, F. and M. McDermott, Genetics of type 1 diabetes mellitus. Genes and immunity, 2002. 3(5): p. 235-249.
1 2 3 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.
1 2 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.
1 2 3 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.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.

[a_genome-wide_search-1] 1 2 Davies, J.L., et al., A genome-wide search for human type 1 diabetes susceptibility genes. Nature, 1994. 371(6493): p. 130-136.

[IDDM-2] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Zollo, M., P. Dear, and F. Pociot, Insulin‐dependent Diabetes Mellitus (IDDM): Identifying the Disease‐causing Gene at the IDDM11 Locus. eLS.

[Familial_aggregation-3] 1 2 3 4 5 Harjutsalo, V., Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland. 2007.

[Genetic-4] 1 2 Pociot, F. and M. McDermott, Genetics of type 1 diabetes mellitus. Genes and immunity, 2002. 3(5): p. 235-249.

[Susceptibility-5] 1 2 3 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.

[Maternal_isodisomy-6] 1 2 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.

[No_evidence-7] 1 2 3 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.