|Coordinate||82,286,967 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||insulin receptor substrate 1|
|Chromosomal Location||82,233,101-82,291,416 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]
PHENOTYPE: Homozygotes for targeted null mutations exhibit 50 percent reductions in body weights at birth and at 4 months of age, impaired glucose tolerance, and mild insulin and IGF-1 resistance. [provided by MGI curators]
|Amino Acid Change||Leucine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000063795]|
AA Change: L1176*
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.9755|
|Is this an essential gene?||Possibly essential (E-score: 0.614)|
|Candidate Explorer Status||CE: excellent candidate; human score: 2.5; ML prob: 0.808|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:40 PM by Anne Murray|
|Record Created||2017-03-21 4:00 PM|
The runt2 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5031 some of which showed reduced body weights compared to wild-type littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 51 mutations. The body weight phenotype was linked to a mutation in Irs1: a T to A transversion at base pair 82,286,967 (v38) on chromosome 1, or base pair 4,473 in the GenBank genomic region NC_000067 encoding Irs1. Linkage was found with a recessive model of inheritance, wherein three variant homozygotes departed phenotypically from 17 homozygous reference mice and 18 heterozygous mice with a P value of 7.09 x 10-8 (Figure 2).
The mutation corresponds to residue 4,473 in the mRNA sequence NM_010570 within exon 1 of 2 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of leucine 1,176 to a premature stop codon (L1176*) in the IRS1 protein.
Irs1 encodes insulin receptor substate-1 (IRS1), one of four members of the IRS family (IRS1 through IRS4). The IRS proteins consist of N-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains followed by long, unstructured C-terminal tails containing numerous tyrosine, serine, and threonine residues [Figure 3; reviewed in (1)]. IRS1 and IRS2 (see the record for dum_dum) have highly similar PH and PTB domains; the two proteins function analogously in insulin receptor (IR; see the record for gummi_bear) signaling (2). IRS1 and IRS2 differ within their respective tail regions. The PH and PTB domains of IRS1 interact with the activated IR and are therefore necessary for insulin-stimulated tyrosine phosphorylation of IRS1 (3-6). Both domains fold into a seven-stranded, antiparallel β-sandwich capped at one end by an α-helix [PDB:1QQG; (7;8)]. The PTB domain binds to the juxtamembrane region of the IR (8); in vitro binding experiments showed that the IRS1 PTB recognizes an NPXpY sequence motif with a hydrophobic residue at pY−8 (6;9). The IRS1 PH domain binds to phosphatidylinositol phosphates, an interaction that may help bring IRS1 to the IR at the cell membrane (7).
IRS1 and IRS2 are regulated by phosphorylation of more than 50 serine/threonine residues within their long, unstructured C-terminal tails (1;10). Depending on the sites affected and the time course of phosphorylation, phosphorylation can have positive or negative regulatory effects on IRS function.
The runt2 mutation results in substitution of leucine 1,176 to a premature stop codon (L1176*) in the IRS1 protein; Leu1176 is within the C-terminal tail.
Please see the record for runt for more information about Irs1.
The insulin signaling pathway regulates glucose uptake and release as well as the synthesis and storage of carbohydrates and lipids. Binding of insulin to the ectodomain of the IR activates the insulin signaling pathway by triggering a conformational change that facilitates IR autophosphorylation of the kinase domain. Phosphorylation of the kinase activation loop stimulates IR catalytic activity. Phosphorylation of the juxtamembrane region of the IR recruits downstream signaling proteins (e.g., IRS1, IRS2, and Shc [see the record for shrine (Shc2)]). IRS1 and IRS2 do not have intrinsic enzyme activity, but function as docking proteins that bind and activate signal transduction proteins (11). Activated IR propagates signaling to activate three main pathways: the MAP kinase, Cbl/CAP, and PI3K pathways (12). For more information about IR-associated signaling, please the record for gummi_bear.
Mutations in IRS1 are associated with noninsulin-dependent diabetes mellitus (OMIM: #125853) (13-15). Degradation of IRS1 contributes to insulin resistance. Prolonged insulin stimulation and subsequent activation of the mTOR signaling pathway promotes IRS degradation by the 26S proteasome (16). A mutation in IRS1 (p.G972R) is a risk factor for coronary artery disease (17). The G972R mutation was also associated with a higher frequency of diabetes mellitus (14.9% among carriers), with a 60% increase of plasma total triglycerides, and with increased total plasma cholesterol levels (17).
Systemic knockout of either IRS1 or IRS2 in mice leads to hyperinsulinemia, impaired glucose tolerance, and reduced insulin sensitivity (18-21). However, distinct phenotypes are also observed in Irs1-/- and Irs2-/- mice. Irs1-/- mice display growth retardation (50 to 60% of WT weight) and their insulin resistance is compensated by β cell hyperplasia so that fasting blood glucose levels are normal in 4-8 week old mice (18;19). Irs1-/- mice also showed higher blood pressures and plasma triglyceride levels with concomitant reduced levels of lipoprotein lipase activity than wild-type mice (22). In contrast, Irs2-/- mice show mild growth retardation (90% of WT weight) and develop diabetes due to a lack of β cell compensation for insulin resistance (20). Mice expressing a spontaneous Irs1 mutation showed reduced body sizes, hearing loss, less serum IGF1 levels, hyperinsulinemia, mild insulin resistance, low bone mineral densities, reduced trabecular and cortical thicknesses, and low bone formation rates (23).
1) 94°C 2:00
The following sequence of 414 nucleotides is amplified (chromosome 1, - strand):
1 gagaccttct cagcacctac tcgggctggc aatacggtgc cctttggagc aggggctgca
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Copps, K. D., and White, M. F. (2012) Regulation of Insulin Sensitivity by serine/threonine Phosphorylation of Insulin Receptor Substrate Proteins IRS1 and IRS2. Diabetologia. 55, 2565-2582.
2. Sun, X. J., Wang, L. M., Zhang, Y., Yenush, L., Myers, M. G.,Jr, Glasheen, E., Lane, W. S., Pierce, J. H., and White, M. F. (1995) Role of IRS-2 in Insulin and Cytokine Signalling. Nature. 377, 173-177.
3. Yenush, L., Makati, K. J., Smith-Hall, J., Ishibashi, O., Myers, M. G.,Jr, and White, M. F. (1996) The Pleckstrin Homology Domain is the Principal Link between the Insulin Receptor and IRS-1. J Biol Chem. 271, 24300-24306.
4. Myers, M. G.,Jr, Grammer, T. C., Brooks, J., Glasheen, E. M., Wang, L. M., Sun, X. J., Blenis, J., Pierce, J. H., and White, M. F. (1995) The Pleckstrin Homology Domain in Insulin Receptor Substrate-1 Sensitizes Insulin Signaling. J Biol Chem. 270, 11715-11718.
5. Voliovitch, H., Schindler, D. G., Hadari, Y. R., Taylor, S. I., Accili, D., and Zick, Y. (1995) Tyrosine Phosphorylation of Insulin Receptor Substrate-1 in Vivo Depends upon the Presence of its Pleckstrin Homology Region. J Biol Chem. 270, 18083-18087.
6. Wolf, G., Trub, T., Ottinger, E., Groninga, L., Lynch, A., White, M. F., Miyazaki, M., Lee, J., and Shoelson, S. E. (1995) PTB Domains of IRS-1 and Shc have Distinct but Overlapping Binding Specificities. J Biol Chem. 270, 27407-27410.
7. Dhe-Paganon, S., Ottinger, E. A., Nolte, R. T., Eck, M. J., and Shoelson, S. E. (1999) Crystal Structure of the Pleckstrin Homology-Phosphotyrosine Binding (PH-PTB) Targeting Region of Insulin Receptor Substrate 1. Proc Natl Acad Sci U S A. 96, 8378-8383.
8. Eck, M. J., Dhe-Paganon, S., Trub, T., Nolte, R. T., and Shoelson, S. E. (1996) Structure of the IRS-1 PTB Domain Bound to the Juxtamembrane Region of the Insulin Receptor. Cell. 85, 695-705.
9. He, W., O'Neill, T. J., and Gustafson, T. A. (1995) Distinct Modes of Interaction of SHC and Insulin Receptor Substrate-1 with the Insulin Receptor NPEY Region Via Non-SH2 Domains. J Biol Chem. 270, 23258-23262.
10. Boura-Halfon, S., and Zick, Y. (2009) Phosphorylation of IRS Proteins, Insulin Action, and Insulin Resistance. Am J Physiol Endocrinol Metab. 296, E581-91.
11. Sun, X. J., Rothenberg, P., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J., and White, M. F. (1991) Structure of the Insulin Receptor Substrate IRS-1 Defines a Unique Signal Transduction Protein. Nature. 352, 73-77.
12. Khan, A. H., and Pessin, J. E. (2002) Insulin Regulation of Glucose Uptake: A Complex Interplay of Intracellular Signalling Pathways. Diabetologia. 45, 1475-1483.
13. Laakso, M., Malkki, M., Kekalainen, P., Kuusisto, J., and Deeb, S. S. (1994) Insulin Receptor Substrate-1 Variants in Non-Insulin-Dependent Diabetes. J Clin Invest. 94, 1141-1146.
14. Almind, K., Bjorbaek, C., Vestergaard, H., Hansen, T., Echwald, S., and Pedersen, O. (1993) Aminoacid Polymorphisms of Insulin Receptor Substrate-1 in Non-Insulin-Dependent Diabetes Mellitus. Lancet. 342, 828-832.
15. Rung, J., Cauchi, S., Albrechtsen, A., Shen, L., Rocheleau, G., Cavalcanti-Proenca, C., Bacot, F., Balkau, B., Belisle, A., Borch-Johnsen, K., Charpentier, G., Dina, C., Durand, E., Elliott, P., Hadjadj, S., Jarvelin, M. R., Laitinen, J., Lauritzen, T., Marre, M., Mazur, A., Meyre, D., Montpetit, A., Pisinger, C., Posner, B., Poulsen, P., Pouta, A., Prentki, M., Ribel-Madsen, R., Ruokonen, A., Sandbaek, A., Serre, D., Tichet, J., Vaxillaire, M., Wojtaszewski, J. F., Vaag, A., Hansen, T., Polychronakos, C., Pedersen, O., Froguel, P., and Sladek, R. (2009) Genetic Variant Near IRS1 is Associated with Type 2 Diabetes, Insulin Resistance and Hyperinsulinemia. Nat Genet. 41, 1110-1115.
16. Shah, O. J., Wang, Z., and Hunter, T. (2004) Inappropriate Activation of the TSC/Rheb/mTOR/S6K Cassette Induces IRS1/2 Depletion, Insulin Resistance, and Cell Survival Deficiencies. Curr Biol. 14, 1650-1656.
17. Baroni, M. G., D'Andrea, M. P., Montali, A., Pannitteri, G., Barilla, F., Campagna, F., Mazzei, E., Lovari, S., Seccareccia, F., Campa, P. P., Ricci, G., Pozzilli, P., Urbinati, G., and Arca, M. (1999) A Common Mutation of the Insulin Receptor Substrate-1 Gene is a Risk Factor for Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 19, 2975-2980.
18. Araki, E., Lipes, M. A., Patti, M. E., Bruning, J. C., Haag, B.,3rd, Johnson, R. S., and Kahn, C. R. (1994) Alternative Pathway of Insulin Signalling in Mice with Targeted Disruption of the IRS-1 Gene. Nature. 372, 186-190.
19. Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., and Satoh, S. (1994) Insulin Resistance and Growth Retardation in Mice Lacking Insulin Receptor Substrate-1. Nature. 372, 182-186.
20. Withers, D. J., Gutierrez, J. S., Towery, H., Burks, D. J., Ren, J. M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G. I., Bonner-Weir, S., and White, M. F. (1998) Disruption of IRS-2 Causes Type 2 Diabetes in Mice. Nature. 391, 900-904.
21. Kido, Y., Burks, D. J., Withers, D., Bruning, J. C., Kahn, C. R., White, M. F., and Accili, D. (2000) Tissue-Specific Insulin Resistance in Mice with Mutations in the Insulin Receptor, IRS-1, and IRS-2. J Clin Invest. 105, 199-205.
22. Abe, H., Yamada, N., Kamata, K., Kuwaki, T., Shimada, M., Osuga, J., Shionoiri, F., Yahagi, N., Kadowaki, T., Tamemoto, H., Ishibashi, S., Yazaki, Y., and Makuuchi, M. (1998) Hypertension, Hypertriglyceridemia, and Impaired Endothelium-Dependent Vascular Relaxation in Mice Lacking Insulin Receptor Substrate-1. J Clin Invest. 101, 1784-1788.
23. DeMambro, V. E., Kawai, M., Clemens, T. L., Fulzele, K., Maynard, J. A., Marin de Evsikova, C., Johnson, K. R., Canalis, E., Beamer, W. G., Rosen, C. J., and Donahue, L. R. (2010) A Novel Spontaneous Mutation of Irs1 in Mice Results in Hyperinsulinemia, Reduced Growth, Low Bone Mass and Impaired Adipogenesis. J Endocrinol. 204, 241-253.
|Science Writers||Eva Marie Y. Moresco, Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Emre Turer and Bruce Beutler|