Insulin Receptor

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OMIM Number

147670

NCBI Gene ID

3643

Uniprot ID

P06213

Length

182,150 bases

No. of Exons

22

No. of isoforms

2

Protein Name

Insulin receptor

Molecular Mass

156333 Da

Amino Acid Count

1382

Genomic Location

chr19:7,112,264-7,294,413

Gene Map Locus
19p13.2

Description

The insulin receptor is a transmembrane receptor through which the physiological effects of the insulin hormone are achieved. The receptor consists of four polypeptide chains, which come together to form a cylindrical structure. Binding of insulin to this receptor, activates it and induces certain conformational changes, which cause first auto-phosphorylation of the receptor itself, followed by phosphorylation of substrate molecules, including the Insulin Receptor Substrate 1 (IRS1). Phosphorylation of IRS1 and other substrate molecules leads to a cascade of signal transduction and gene activation events, ultimately resulting in the activation of the glucose transporter, Glut4, and its movement from cellular vesicles towards the cell membrane. Glut4 subsequently, mediates the transport of glucose into the cells. Under normal circumstances, once activated by insulin, the insulin-receptor complex is internalized by the cell, and the receptor is thus removed from the membrane. Later, the receptor is recycled back to the membrane, after the insulin part of the complex is destroyed. The uptake of glucose by the cells can be down-regulated by preventing these receptor molecules to return back to the membrane. This situation is seen in cases where there is persistent excess insulin or high blood glucose.

Since the major effect of binding of insulin to its receptor is the uptake of glucose by the cells, defects in the gene encoding for this protein cause 'insulin insensitivity', resulting in disease conditions such as non insulin dependent diabetes mellitus, Rabson-Mendenhall syndrome, leprechaunism, hyperinsulenimic hypoglycemia, or insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN). The INSR gene is expressed maximally in cells that are most responsive to insulin for glucose, lipid and protein metabolism, especially adipose, skeletal muscle and liver.

Molecular Genetics

The insulin receptor gene (INSR) is located on chromosome 19, and with its 22 exons, it spans a total length of a little more than 170 Kb. The gene is transcribed into an mRNA, which exists in many different splice site variants. The protein coded for by this mRNA, is typically made up of 1382 amino acids, weighs about 156KDa, and consists of a linear alpha-beta chain. This protein is called the proreceptor, after it undergoes cleavage of a C-terminal 12 amino acid leader sequence. The proreceptor molecule is later cleaved into the alpha and beta chains after it forms disulfide linkages with another similar proreceptor molecule. The mature protein product, therefore, is a tetramer, which consists of two alpha and two beta polypeptides, and functions as a tyrosine kinase. The ligand binding domains are found on the alpha chains, whereas the beta chains carry the kinase domain for phosphorylation.

The protein itself can be seen in two different isoforms: a long and a short one. The short isoform has higher affinity for insulin, and is expressed in the peripheral nerve, kidney, liver, striated muscles, fibroblasts, skin, spleen, and the lymphocytes.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_000208.4:c.3356G>AUnited Arab EmiratesNC_000019.10:g.7122892C>TLikely PathogenicHyperinsulinemic Hypoglycemia, Familial, 5NG_008852.2:g.176109G>A; NM_000208.4:c.3356G>A; NP_000199.2:p.Arg1119Gln1160859936
NM_000208.4:c.421C>TUnited Arab EmiratesNC_000019.10:g.7267576G>AUncertain SignificanceLikely Pathogenic, PathogenicPineal Hyperplasia, Insulin-Resistant Diabetes Mellitus, and Somatic AbnormalitiesNG_008852.2:g.31425C>T; NM_000208.4:c.421C>T; NP_000199.2:p.Arg141Trp1555689823439835

Other Reports

Morocco

Maassen et al. (2003) studied a patient of Moroccan origin, who presented at the age of 17-years with severe insulin resistance. Analysis of the DNA revealed her to be homozygous for the Arg252His mutation. Studies on CHO cell lines transfected with this gene, followed by western blot analysis, showed that the mutation interfered with receptor processing and its surface expression, and also that the patient showed very low binding of insulin to the fibroblasts. Maassen et al. (2003) noted that although the reduction in insulin binding in this patient was as severe as in Leprecahunism, the patient did not develop Leprechaunism, but only went on to develop Type A Insulin Resistanc; probably due to a minimal insulin induced signaling still remaining in the mutated receptor or endogenous IGF-1 receptors.

Qatar

Hone et al. (1995) studied a Qatari patient, born to consanguineous parents, who died at the age of four months due to Leprechaunism. All 22 exons of the INSR gene of this patient were analyzed by DDGE, followed by direct sequencing of suspected exons. A mutation was detected in exon 13, in which 13 base pairs were deleted, resulting in a frame shift and introduction of a premature stop codon. The transcribed protein therefore, lacked both the transmembrane and the tyrosine kinase domains. The patient was found to be homozygous for this effectively null mutation.

Yemen

Hone et al. (1994) studied the insulin receptor gene in a large Yemeni consanguineous family in UAE, in which five of nine children had clinical symptoms of insulin resistance. Denaturing gradient gel electrophoresis was used to screen all 22 exons of the INSR gene, and it revealed an abnormal migration pattern in exon 2. Direct sequencing of this exon revealed a C to G transversion, which resulted in a Ile119Met mutation. RFLP using NlaIII was used to confirm this mutation. All five of the patients were found to be homozygous for this mutation, whereas both parents and two of the four unaffected siblings were heterozygous. The heterozygous father showed mild insulin resistance. Lod score calculated for this pedigree supported the conclusion that this Ile119Met mutation was responsible for the disease condition in this family. Hone et al. (1994) purported that the mutation would result in defective intracellular transport and post-translational processing of the receptor, as well as interfere with the ligand binding.

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