|Coordinate||3,161,770 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||insulin receptor|
|Synonym(s)||IR-A, IR-B, D630014A15Rik, 4932439J01Rik, IR, CD220|
|Chromosomal Location||3,122,061-3,279,617 bp (-)|
FUNCTION: This gene encodes a member of the receptor tyrosine kinase family of transmembrane signaling proteins that play important roles in cell differentiation, growth and metabolism. The encoded preproprotein undergoes proteolytic processing to generate alpha and beta chains that form a disulfide-linked heterodimer which, in turn homodimerizes to form a mature, functional receptor. Mice lacking the encoded protein develop severe hyperglycemia and hyperketonemia, and die within a couple of days after birth as a result of diabetic ketoacidosis. [provided by RefSeq, Aug 2016]
PHENOTYPE: Null mutants grow slowly and die by 7 days of age with ketoacidosis, high serum insulin and triglycerides, low glycogen stores and fatty livers. Tissue specific knockouts show milder lipid metabolism anomalies. Point mutation heterozygotes exhibit hyperglycemia, hyperinsulinemia and glucosuria. [provided by MGI curators]
|Amino Acid Change||Serine changed to Proline|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000088837]|
AA Change: S1084P
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.9433|
|Is this an essential gene?||Probably essential (E-score: 0.846)|
|Candidate Explorer Status||CE: excellent candidate; human score: 3; ML prob: 0.58|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:48 PM by Diantha La Vine|
|Record Created||2014-06-15 1:08 PM by Emre Turer|
The gummi bear phenotype was identified among G3 mice of the pedigree R0480, some of which showed susceptibility to low-dose DSS-induced colitis at day 7 (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 113 mutations. Both of the above anomalies were linked by continuous variable mapping to a mutation in Insr: a T to C transition at base pair 3,161,770 (v38) on chromosome 8, or base pair 117,880 in the GenBank genomic region NC_000074 encoding Insr. The strongest association was found with a recessive model of inheritance to the raw DSS-induced susceptibility phenotype, wherein one variant homozygote departed phenotypically from 12 homozygous reference mice and 8 heterozygous mice with a P value of 2.779 x 10-8 (Figure 2).
The mutation corresponds to residue 3,739 in the mRNA sequence NM_010568 within exon 17 of 21 total exons.
The mutated nucleotide is indicated in red. The mutation results in a serine (S) to proline (P) substitution at position 1,084 (S1084P) in the InsR protein, and is strongly predicted by Polyphen-2 to be probably damaging (score = 1.000).
The DSS-induced colitis phenotype was verifed by CRISPR-mediated replacement of the gummi_bear Insr mutation (P = 1.095 x 10-14; Figure 3).
Insr encodes the insulin receptor (IR), a member of the receptor tyrosine kinase family. The IR forms either a heterodimer comprised of an extracellular α subunit and a membrane-spanning β subunit (αβ), or a heterotetramer of two α and two β subunits (α2β2); the α and β subunits are both coded by Insr. The α and β subunits are joined by disulfide bonds, which are proteolytically processed at a precursor processing enzyme cleavage site to generate the individual subunits (1;2). IR can also form a heterodimer/heterotetramer (Insrαβ/Igf1rαβ) with insulin-like growth factor-1 receptor (IGF-1R), which alters the selectivity and affinity for insulin and IGF-1 (3). IR also can form a hybrid complex with Met, a receptor for hepatocyte growth factor (HGF) (4). The IR/Met hybrid can strongly activate IR-associated signaling cascades.
IR has a 27-amino acid signal sequence (Figure 4). The α subunit has two leucine-rich domains, a cysteine-rich domain, a fibronectin type III (FnIII) domain, a partial FnIII domain, and a long carboxy-terminal segment that has the furin cleavage site (5;6). The β subunit begins (after a short amino-terminal segment) with the completion of the partial FnIII domain of the α subunit, a third FnIII domain, a transmembrane domain, a juxtamembrane region, a tyrosine kinase domain, and a carboxy-terminal region. The ectodomain of the IR forms an antiparallel “inverted V” [Figure 5; PDB: 4ZXB; (6;7)]. One leg of the V shape is formed from the first leucine-rich domain, the second cysteine-rich region, and the second leucine-rich domain (6). The second leg of the V is comprised of the three FNIII domains. Insulin binding is mediated by two sites in the ectodomain (8). The first site is formed by the first leucine-rich domain in one α subunit and the C-terminal segment of the other α subunit of α2β2 IR. The second site involves loops from the first and second FnIII domains of the other αβ half-receptor.
The IR kinase domain has a canonical kinase architecture with N- and C-lobes. The N-lobe has a five-stranded β sheet and a single α helix (αC), while the C-lobe is mainly helical. The C-lobe has most of the catalytic residues within the catalytic and activation loops. An α helix (αJ) at the carboxy-terminal end of the C-lobe is unique to the IR. The function of the αJ helix is unknown, but in a complex with the phosphastase PTP1B, the αJ helix is part of the phosphatase binding site (9). The kinase activity of the IR is regulated by phosphorylation of the activation loop (amino acids 1150 to 1172) in the C-lobe. Tyr1158, Tyr1162, and Tyr1163 within the activation loop are autophosphorylated after binding of insulin to the ectodomain.
INSR undergoes alternative splicing of exon 11 to generate two isoforms that differ by exclusion (isoform A; IR-A) or inclusion (isoform B; IR-B) of a 12- amino-acid sequence in the carboxy-terminal part of the α subunit (10). IR-A is predominantly expressed in fetal tissues, brain and leukocytes, while IR-B is highly expressed in the liver (11). Similar amounts of IR-A and IR-B are expressed in placenta, skeletal muscle, and adipose tissue (11). IR-A has higher affinity for both insulin and IGF-2 as well as a higher rate of internalization than IR-B, and IR-A is often upregulated in cancers (12).
The gummi_bear mutation results in a serine (S) to proline (P) substitution at position 1,084 (S1084P), which is within the kinase domain of the β subunit.
The IR is ubiquitously expressed.
The insulin signaling pathway regulates glucose uptake and release as well as the synthesis and storage of carbohydrates and lipids (Figure 6). Binding of insulin to the IR activates IR intrinsic tyrosine kinase activity, which propagates signaling to activate three main pathways: the MAP kinase, Cbl/CAP, and PI3K pathways (13). Insulin growth factor 1 (IGF1) and IGF2 are also traditional IR ligands. Binding of insulin to the ectodomain of 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., insulin receptor substrate proteins [Irs1 (see the record for runt) and Irs2 (see the record for dum_dum)] and Shc [see the record for shrine (Sch2)]). Shc activates the Shc-Grb2-Sos-Ras-Raf-MAPK pathway, which controls cellular proliferation and gene transcription. Phosphorylated IRS1 docks with SH2 domain-containing proteins and mediates signal transduction to downstream factors. IRS1 and IRS2 activate many similar downstream pathways (e.g., the PI3K and Akt pathways), but are not functionally redundant. The IRS proteins recruit and activate PI3K, which leads to the generation of the second messenger PIP3. PIP3 recruits and activates PDK-1, which phosphorylates and activates Akt and atypical PKCs. Akt regulates glucose transport, lipid synthesis, gluconeogenesis, glycogen synthesis, cell cycle, and survival. Activated IR can also phosphorylate several “alternative” substrates, some of which provide docking sites for recruitment of other downstream signaling proteins (Table 1).
Table 1. Select alternative substrates of IR
Several factors negatively regulate IR-associated signaling [reviewed in (36)]. Adaptor proteins Grb7, Grb10, and Grb14 (37-40) reduce IR activity through direct interaction. The Grb proteins are recruited to the IR whereby they compete with IRS for IR binding, inhibiting IR activity. The protein tyrosine phosphatases PTP1B, PTP1C, TCPTP, and PTPRF dephosphorylate the IR, subsequently negatively regulating its activity (41-43). The phosphatases are recruited to the IR through their SH2 domains after insulin stimulation and IR autophosphorylation. Suppressors of cytokine signaling (SOCS) proteins (SOCS1 [see the record for minipad], SOCS3, and SOCS6) directly interact with the IR to block downstream signal transduction by competing for binding to the IR (44;45). Protein kinase C isoforms (PKCδ [see the record for Rigged] and PKCε [see the record for pinnacles]) also negatively regulate IR-associated signaling (46). The PKCs phosphorylate the IR, which lowers its tyrosine kinase activity (46).
Mutations in INSR are associated with insulin-resistant diabetes mellitus with acanthosis nigricans [OMIM: #610549; (47-49)]. Acanthosis nigricans is a skin condition characterized by areas of discoloration in body folds and creases often in the armpits, groin, and neck. INSR mutations are also linked to familial hyperinsulinemic hypoglycemia 5 [HHF5; OMIM: #609968; (50)], leprechaunism [alternatively, Donohue syndrome; OMIM: #246200; (51-55)], and Rabson-Mendenhall syndrome [OMIM: #262190; (56;57)]. Patients with leprechaunism have growth delays, skin abnormalities, reduced muscle mass, phallic enlargement, and insulin resistance. Patients with Rabson-Mendenhall syndrome exhibit dental and skin abnormalities, abdominal distention, and phallic enlargement.
Insr-deficient (Insr-/-) mice exhibited postnatal lethality within 72 hours after birth due to hyperglycemia, diabetic ketoacidosis, and hepatic steatosis (58;59). Insr-/- mice exhibit reduced body weights compared to wild-type controls. Rescue of IR expression in brain, liver, and pancreatic beta cells rescued the Insr-/- mice from neonatal death, prevented diabetes in most mice, and normalized adipose tissue content, lifespan, and reproductive function (60). Heterozygous Insr mice (Insr+/-) mice exhibited increased circulating insulin levels and insulin resistance (61;62). Heterozygous mice for an ENU-induced Insr alleles exhibited hyperglycemia and increased circulating insulin levels (MGI). Mice with muscle-specific IR knockout showed increased fat mass, serum triglycerides, and fatty acids; however blood glucose, serum insulin, and glucose tolerance were normal (63). Mice with fat-specific IR knockout showed reduced fat mass, were protected from age-related obesity and obesity-related glucose intolerance, and had increased mean life spans (64;65). Mice with brown adipose tissue-specific IR knockout showed an age-dependent loss of interscapular brown fat and developed an insulin-secretion defect resulting in a progressive glucose intolerance, without insulin resistance (66). Mice with pancreatic beta cell-specific IR knockout showed loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance (67). Mice with hepatocyte-specific IR knockout showed insulin resistance, glucose intolerance, hyperinsulinemia, and a failure of insulin to suppress hepatic glucose production (68). Mice with cardiomyocyte-specific IR knockout showed subendocardial fibrosis and left ventricular dysfunction four weeks after a transverse aortic constriction (69).
The role of IR-associated signaling in colonic inflammation is unclear. Increased IGF bioactivity leads to increased epithelial proliferation and mucosal barrier repair, thereby lessening inflammation (70). Aberrant IGF bioactivity in the gummi_bear mice may be leading to reduced epithelial proliferation and mucosal barrier repair after exposure of the mice to DSS.
1) 94°C 2:00
The following sequence of 786 nucleotides is amplified (chromosome 8, - strand):
1 tgcagggaag acagttccca aactagtagt ggcatgttac gagacaaatg cttgaagaaa
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
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|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Emre Turer and Bruce Beutler|