IDDM11

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Insulin-dependent (type I) diabetes mellitus (IDDM) is a genetic heterogenous 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]

Contents

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]

Human chromosome 14 - 550 bphs Human chromosome 14 - 550 bphs.png
Human chromosome 14 - 550 bphs

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

LocusChrosomeCandidate gene/ Microsatellites
IDDM16p21 HLA-DR/ DQ
IDDM211p15.5INS-VNTR
IDDM315q26D15S107
IDDM411q13MDU1, ZFM1, RT6, FADD, LRP5
IDDM56q25ESR, MnSOD
IDDM618q12-q21D18S487, D18S64, JK (Kidd locus)
IDDM72q31D2S152, IL-1, NEUROD, GALNT3, HOXD8
IDDM86q25-27D6S264, D6S446, D6S281
IDDM93q21-25D3S1303, D3S1589, D3S3606
IDDM1010p11-q11D10S193, D10S208, D10S588, D10S1426
IDDM1114q24.3-q31D14S67
IDDM122q33 CTLA-4, CD28
IDDM132q34D2S137, D2S164, IGFBP2, IGFBP5
IDDM142q34-q35NCBI # 3413
IDDM156q21D6S283, D6S434, D6S1580
IDDM1614q32 IGH
IDDM1710q25D10S1750-D10S1773
IDDM185q31.1-33.1 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]

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]

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

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when pancreatic cells are destroyed by the body's immune system. In healthy persons, beta cells produce insulin. Insulin is a hormone required by the body to store and convert blood sugar into energy. T1D results in high blood sugar levels in the body prior to treatment. Common symptoms include frequent urination, increased thirst, increased hunger, weight loss, and other complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. While some cases take longer, symptoms usually appear within weeks or a few months.

<span class="mw-page-title-main">Chromosome 6</span> Human chromosome

Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 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.

In genetics, 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.

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<span class="mw-page-title-main">HLA-DR</span> Subclass of HLA-D antigens that consist of alpha and beta chains

HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.

<span class="mw-page-title-main">HLA-DQ</span> Cell surface receptor protein found on antigen-presenting cells.

HLA-DQ (DQ) is a cell surface receptor protein found on antigen-presenting cells. It is an αβ heterodimer of type MHC class II. The α and β chains are encoded by two loci, HLA-DQA1 and HLA-DQB1, that are adjacent to each other on chromosome band 6p21.3. Both α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus 4 isoforms of DQ. The DQ loci are in close genetic linkage to HLA-DR, and less closely linked to HLA-DP, HLA-A, HLA-B and HLA-C.

<span class="mw-page-title-main">HLA-DQ9</span>

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.

<span class="mw-page-title-main">CAPN10</span> Protein-coding gene in humans

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<span class="mw-page-title-main">BAT2</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">FOXN3</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">C4A</span> Protein-coding gene in the species Homo sapiens

Complement C4-A is a kind of the Complement component 4 protein that in humans is encoded by the C4A gene.

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<span class="mw-page-title-main">CDKAL1</span> Protein-coding gene in humans

CDKAL1 is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1. This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells. CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.

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References

  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.
  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.
  3. 1 2 3 4 5 Harjutsalo, V., Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland. 2007.
  4. 1 2 Pociot, F. and M. McDermott, Genetics of type 1 diabetes mellitus. Genes and immunity, 2002. 3(5): p. 235-249.
  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.
  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.
  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.