HGNC Approved Gene Symbol: INSR
SNOMEDCT: 111307005, 237606005, 33559001, 44054006, 48606007, 763325000; ICD10CM: E11;
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:7,112,265-7,294,414 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Diabetes mellitus, insulin-resistant, with acanthosis nigricans | 610549 | 3 | |
| Donohue syndrome | 246200 | Autosomal recessive | 3 | |
| Hyperinsulinemic hypoglycemia, familial, 5 | 609968 | Autosomal dominant | 3 | |
| Rabson-Mendenhall syndrome | 262190 | Autosomal recessive | 3 |
Insulin receptor is a tetramer of 2 alpha and 2 beta subunits. The alpha and beta subunits are coded by a single gene and are joined by disulfide bonds, a mechanism parallel to that of its ligand, insulin (INS; 176730) (Rubin, 1984).
Ullrich et al. (1985) deduced the entire 1,370-amino acid sequence of the insulin receptor from a cDNA clone. The precursor starts with a 27-amino acid signal sequence, followed by the receptor alpha subunit, a precursor processing enzyme cleavage site, then the beta subunit containing a single 23-amino acid transmembrane sequence.
Caro et al. (1988) demonstrated differences in molecular mass, carbohydrate composition, and antigenicity between the insulin receptor alpha subunit in liver and in muscle and adipose tissue, the 2 major peripheral target tissues of insulin. Moreover, the same authors showed that the insulin-stimulated tyrosyl kinase activity is greater in muscle than in liver or adipose tissue. There are sequence homologies to EGF receptor (131550).
Two insulin receptor mRNA transcripts resulting from alternative splicing of exon 11 in the receptor gene are expressed in a highly regulated tissue-specific fashion. Benecke et al. (1992) studied the relative abundance of these 2 mRNA species in human tissues; the one containing exon 11 shows a marked predominance in liver, whereas the isoform in which exon 11 has been spliced out shows a comparable predominance in leukocytes. Similar amounts of the 2 variants were found in placenta, skeletal muscle, and adipose tissue. No significant differences were found between control and diabetic subjects.
Due et al. (1986) presented evidence that the class I MHC heavy chain (HLA-A, HLA-B, HLA-C; see 142800) is a structural subunit of the insulin receptor. This broadens the range of biologic functions possible for histocompatibility antigens. Interaction of class I HLA molecules with glucagon receptors (e.g., 138033) and epidermal growth factor receptors (e.g., 131550) has also been demonstrated. Due et al. (1986) favored the hypothesis that the beta-2-microglobulin molecule (B2M; 109700) is replaced by the insulin receptor when it associates with the MHC class I heavy chain. Kittur et al. (1987) presented evidence for associations between HLA antigens and specific insulin-binding sites on human B lymphocytes. They cited experiments demonstrating coprecipitation of a fraction of insulin receptors with class I and class II MHC antigens. Thus, in addition to other functions of the MHC antigens, they may affect the functioning of, or themselves serve as, cell surface receptors.
Williams et al. (1990) created a mutant form of the INSR gene by site-directed mutagenesis in order to study the effects of mutation on functions of the receptor.
Christiansen et al. (1991) used data from electron microscopy to deduce a model for a quaternary structure of the insulin receptor of human placenta.
Using a yeast 2-hybrid system, Dey et al. (1998) identified a regulatory subunit of phosphatidylinositol 3-kinase, PIK3R3 (606076), as a binding partner of INSR. They concluded that PIK3R3 interacts with IGF1R (147370) and INSR in a kinase-dependent manner, providing an alternative pathway for the activation of PI3K by these 2 receptors.
The protein tyrosine phosphatase PTP1B (176885) is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine (ptyr) residues of the INSR kinase activation segment, or IRK. By integrating crystallographic, kinetic, and PTP1B peptide-binding studies, Salmeen et al. (2000) defined the molecular specificity of this reaction. Extensive interactions are formed between PTP1B and the IRK sequence encompassing the tandem ptyr residues at positions 1162 and 1163, such that ptyr1162 is selected at the catalytic site and ptyr1163 is located within an adjacent ptyr-recognition site. This selectivity is attributed to the 70-fold greater affinity for tandem ptyr-containing peptides relative to mono-ptyr peptides and predicts a hierarchical dephosphorylation process. Many elements of the PTP1B-IRK interaction are unique to PTP1B, indicating that it may be feasible to generate specific, small molecule inhibitors of this interaction to treat diabetes and obesity.
Leibiger et al. (2001) showed that insulin activates the transcription of its own gene and that of the beta-cell glucokinase gene (GCK; 138079) by different mechanisms. Whereas INS gene transcription is promoted by signaling through INSR type A (without exon 11), PI3K class IA (see 171833), and the 70-kD S6 kinase, insulin stimulates the beta-cell GCK gene by signaling via INSR type B (with exon 11), PI3K class II (see 602838)-like activity, and protein kinase B (164730). These data provided evidence for selectivity in insulin action via the 2 INSR isoforms, the molecular basis being preferential signaling through different PI3K and protein kinases.
Rajala and Anderson (2001) sought to identify the tyrosine-phosphorylated protein(s) in the bovine rod outer segments (ROS) that are associated with PI3K. They concluded that tyrosine phosphorylation of the beta subunit of the insulin receptor is involved in the regulation of PI3K activity in the ROS.
By purification and molecular characterization, Brunetti et al. (2001) found that HMGIY (600701) bound and activated 2 AT-rich regions in the INSR promoter. Knockdown of HMGIY via antisense RNA reduced surface expression of INSR in 2 human cell lines that normally express high INSR levels. Conversely, transfection of HMGIY elevated surface expression of INSR in 2 cell lines that normally express little INSR.
Decreased affinity of numerically normal insulin receptor binding sites has been reported in patients with myotonic dystrophy (Tevaarwerk et al., 1979). Myotonic dystrophy is often associated with disturbances in insulin response. In muscle from patients with myotonic dystrophy type 1 (DM1; 160900), altered insulin receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the myotonic dystrophy phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of DM. Savkur et al. (2004) demonstrated that comparable splicing abnormalities occur in DM2 (602668) muscle before the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions.
Song et al. (2013) showed in mice that muscle-specific mitsugumin-53 (MG53; 613288) mediates the degradation of the insulin receptor and insulin receptor substrate-1 (IRS1; 147545), and when upregulated causes metabolic syndrome featuring insulin resistance, obesity, hypertension, and dyslipidemia. Mg53 expression is markedly elevated in models of insulin resistance, and Mg53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of Mg53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, Irs1, and insulin signaling integrity. Mechanistically, Mg53 acts as an E3 ligase targeting the insulin receptor and Irs1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. Song et al. (2013) concluded that these findings defined MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.
Seino et al. (1989) found that the INSR gene spans more than 120 kb and has 22 exons. The 11 exons encoding the alpha subunit are dispersed over more than 90 kb, whereas the 11 exons encoding the beta subunit are located together in a region of about 30 kb. Three transcriptional initiation sites were identified, located 276, 282, and 283 bp upstream of the translation initiation site.
Brunetti et al. (2001) stated that the promoter region of INSR has no TATA or CAAT boxes, but is extremely GC rich. In addition, they identified 2 functional AT-rich sequences in the INSR promoter that were bound and activated by HMGIY.
Crystal Structure
McKern et al. (2006) presented the crystal structure at 3.8-angstrom resolution of the IR-A ectodomain dimer of the insulin receptor, complexed with 4 antigen-binding fragments (Fabs) from the monoclonal antibodies 83-7 and 83-14, grown in the presence of a fragment of an insulin (176730) mimetic peptide. The structure reveals the domain arrangement in the disulfide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is different from previous models. It shows that the 2 L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.
Lou et al. (2006) reported the crystal structure of the first 3 domains of INSR at 2.3-angstrom resolution and compared it with the structure of the corresponding fragment of IGF1R. They observed notable differences in the regions governing ligand specificity and binding.
Menting et al. (2013) presented a view of the interaction of insulin with its primary binding site on the insulin receptor on the basis of 4 crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich repeat domain (L1) of insulin receptor is sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alpha-CT) segment, which is itself remodeled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alpha-CT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases.
With in situ hybridization and Southern blot analysis of somatic cell hybrid DNA, Yang-Feng et al. (1985) assigned the insulin receptor gene to 19p13.3-p13.2. This site is involved in a nonrandom translocation in pre-B-cell acute leukemia. The t(1;19) was demonstrated by several workers (e.g., Williams et al., 1984) in this childhood form of acute lymphoblastic leukemia which responds poorly to treatment. The cells produce cytoplasmic but not cell-surface immunoglobulin heavy chains. Shaw et al. (1986) concluded from linkage studies that INSR is very close to C3 (120700) but far from DM (160900). By fluorescence in situ hybridization, Trask et al. (1993) assigned the INSR gene to 19p13.3. By simultaneous mapping of multiple probes, they were able to achieve a more refined assignment than was possible when a single probe or a few probes were mapped.
Taylor et al. (1986) concluded that a patient with Donohue syndrome (246200) and extreme insulin resistance was a genetic compound, i.e., that each parent had transmitted to the proband a different defect of the insulin receptor (see 147670.0002). The patient, referred to as leprechaun/Ark-1, had an 80 to 90% decrease in the number of insulin receptors in circulating monocytes. Although the receptors on Epstein-Barr virus-transformed lymphocytes from the patient were normal in number, they showed decreased sensitivity to changes in temperature and pH. The father, who had a moderate degree of insulin resistance, resembled the patient in that his monocytes had a 60 to 80% decrease in the number of insulin receptors. Binding of the father's EB virus-transformed lymphocytes was normal. The mother had normal sensitivity to insulin and a normal number of insulin receptors on circulating monocytes. On the other hand, insulin receptors on the mother's EB virus-transformed lymphocytes were qualitatively abnormal, resembling closely the daughter's cultured cells. The father, who was heterozygous for the nonsense mutation, showed a moderate degree of insulin resistance. Ojamaa et al. (1988) found marked reduction in the level of receptor mRNA in a patient with Donohue syndrome.
Kadowaki et al. (1988) raised the question of whether mutations in the insulin receptor gene may account for the insulin resistance in some patients with noninsulin-dependent diabetes mellitus (NIDDM, T2D; 125853). Taira et al. (1989) suggested that many instances of NIDDM may be due to relatively minor mutations of the insulin receptor gene that cause slightly decreased affinity of the receptor for insulin or a slightly decreased kinase activity; in these cases, environmental factors such as obesity may trigger the onset of diabetes.
Discussing the mechanisms of insulin resistance, Moller and Flier (1991) and Taylor et al. (1991) diagrammed the structure of the human insulin receptor and indicated the position of known point mutations. Taylor et al. (1991) divided mutations in the INSR gene into 5 classes: class 1, impaired receptor biosynthesis; class 2, impaired transport of receptors to the cell surface; class 3, decreased affinity of insulin binding; class 4, impaired tyrosine kinase activity; and class 5, accelerated receptor degradation.
Among 22 unrelated women with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism; 610549), Moller et al. (1994) identified only 1 mutation in the INSR gene: arg1174 to gln (147670.0030). Moller et al. (1994) concluded that mutation in the INSR gene is a rare cause of the type A syndrome of extreme insulin resistance.
't Hart et al. (1999) studied random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies to determine the prevalence of variants in NIDDM candidate genes. The val985-to-met (147670.0029) INSR variant was found at frequencies of 4.4 and 1.8%, respectively, in NIDDM and normoglycemic patients.
McCarthy et al. (2001) genotyped 24 single-nucleotide polymorphisms (SNPs) within the 19p13 region in a Caucasian population comprising 827 unrelated cases of typical migraine (607508). Five SNPs within the insulin receptor gene showed significant association with migraine. Functional studies of the INSR SNPs showed no effect on mRNA levels or splicing in peripheral blood leukocytes or on binding of insulin to mononuclear cells. The authors speculated on possible mechanisms by which the INSR could play a role in the pathogenesis of migraine.
Longo et al. (2002) reported 6 patients and correlated mutations in the insulin receptor gene with survival. Patients with Donohue syndrome were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor, and their cells had markedly impaired insulin binding (less than 10% of controls). Mutations in their insulin receptor gene inserted premature stop codons resulting in decreased levels of mature mRNA, or alternatively affected the extracellular domain of the receptor. Three patients with Rabson-Mendenhall syndrome had at least 1 missense mutation in the intracellular domain of the insulin receptor. Expression studies in CHO cells indicated that several mutations markedly impaired insulin binding (less than 5% of control), while others retained significant insulin-binding activity. The authors concluded that mutations in the insulin receptor retaining residual insulin-binding activity correlated with prolonged survival in a series of patients with extreme insulin resistance.
In all affected members of a 3-generation Danish family with hyperinsulinemic hypoglycemia (see HHF5, 609968), Hojlund et al. (2004) identified heterozygosity for a point mutation in the insulin receptor gene (147670.0030). The mutation was not found in any unaffected family members. The proband's sister, who had moderate symptoms of hypoglycemia, showed mild skin pigmentation in the axillae, increased total and free serum levels of testosterone, and polycystic ovaries.
Foti et al. (2005) reported 4 patients with insulin resistance and type II diabetes in whom cell-surface insulin receptors were decreased and INSR gene transcription was impaired although the INSR genes were normal. In these individuals, expression of HMGA1 (600701) was markedly reduced; restoration of HMGA1 protein expression in their cells enhanced INSR gene transcription and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Foti et al. (2005) concluded that defects in HMGA1 may cause decreased insulin receptor expression and induce insulin resistance.
In genetically obese mice with insulin resistance, Le Marchand-Brustel et al. (1985) found a defect in the tyrosine kinase activity of insulin receptor.
Complete lack of insulin receptors due to mutations of the insulin receptor gene results in severe growth retardation and mild diabetes. In mice, targeted inactivation of insulin receptor substrate-1 (147545) leads to inhibition of growth and mild resistance to the metabolic actions of insulin. To address the question of whether both metabolic and growth-promoting actions of insulin are mediated by the insulin receptor, Accili et al. (1996) generated mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells. Unlike human patients lacking insulin receptors, mice homozygous for a null allele of the insulin receptor gene were born at term with apparently normal intrauterine growth and development. Within hours of birth, however, homozygous null mice developed severe hyperglycemia and hyperketonemia, and died as a result of diabetic ketoacidosis within 48 to 72 hours. The authors considered the data consistent with a model in which the insulin receptor functions primarily to mediate the metabolic actions of insulin.
To determine the contribution of muscle insulin resistance to the metabolic phenotype of diabetes, Bruning et al. (1998) used the Cre-loxP system to disrupt the mouse Insr gene in mouse skeletal muscle. The muscle-specific Insr knockout mice exhibited a muscle-specific reduction greater than 95% in receptor content and early signaling events. The mice displayed elevated fat mass, serum triglycerides, and free fatty acids, but blood glucose, serum insulin, and glucose tolerance were normal. Thus, insulin resistance in muscle contributes to the altered fat metabolism associated with type II diabetes, but tissues other than muscle appear to be more involved in insulin-regulated glucose disposal than previously recognized.
To determine whether insulin signaling has a functional role in the pancreatic beta cell, Kulkarni et al. (1999) used the Cre-loxP system to specifically inactivate the mouse Insr gene in the beta cells. Expression of Cre using a pancreatic beta cell-specific rat insulin promoter resulted in efficient recombination of a loxP-containing Insr gene in the beta cells. Mice lacking the beta-cell insulin receptor showed a loss of first-phase insulin secretion in response to glucose, but not to arginine, similar to that observed in humans with type II diabetes. These mice also showed a progressively impaired glucose tolerance over 6 months. The data indicated an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggested that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type II diabetes.
To investigate the effect of the loss of direct insulin action in liver, Michael et al. (2000) used the Cre-loxP system to inactivate the Insr gene in hepatocytes. Liver-specific Insr-knockout (LIRKO) mice exhibited dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations were paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the livers of knockout mice exhibited morphologic and functional changes, and the metabolic phenotype became less severe. Thus, the authors concluded that insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function.
Bruning et al. (2000) created mice with a neuron-specific disruption of the Insr gene (NIRKO). Inactivation of the insulin receptor had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone (see 152780). Thus, insulin receptor signaling in the central nervous system plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.
Belke et al. (2002) generated mice with a cardiomyocyte-specific Insr- knockout (CIRKO), using cre/loxP recombination. Hearts of CIRKO mice were 20 to 30% smaller because of decreased postnatal hypertrophy of cardiomyocytes; they had persistent expression of the fetal beta-myosin heavy chain isoform, approximately half the normal expression of glucose transporter-1 (GLUT1; 138140), and a 2-fold increase in GLUT4 expression. Cardiac glucose uptake was increased in vivo, glycolysis was increased in isolated working hearts, and there was reduced expression of enzymes that catalyze mitochondrial beta-oxidation, leading to decreased fatty acid oxidation rates.
In brown adipose tissue-specific Insr-knockout mice, Guerra et al. (2001) observed age-dependent profound brown fat atrophy concomitant with the development of fasting hyperglycemia and impaired glucose tolerance. Guerra et al. (2001) concluded that the insulin receptor plays a direct role in brown fat adipogenesis and suggested that brown adipose tissue is involved in the regulation of insulin secretion and glucose homeostasis. An expression of concern was published for this article because of questions regarding Figure 3, A-C and Figure 4, A and B. The original data supporting these figures was no longer available.
Using the Cre-loxP system, Bluher et al. (2002) generated fat-specific Insr-knockout (FIRKO) mice which they found to have reduced fat mass and loss of the normal relationship between plasma leptin and body weight. The mice were also protected against age-related and hypothalamic lesion-induced obesity and obesity-related glucose intolerance. Using histologic and gene expression studies, Bluher et al. (2002) observed that the conditional knockout mice exhibited polarization of adipocytes into populations of large and small cells, which differed in protein expression pattern. Bluher et al. (2002) concluded that insulin signaling in adipocytes is critical for development of obesity and its associated metabolic abnormalities.
Bluher et al. (2003) generated mice with FIRKO. Growth curves were normal in male and female FIRKO mice from birth to 8 weeks of age. Starting at 3 months of age, FIRKO mice maintained 15 to 25% lower body weights and a 50 to 70% reduction in fat mass throughout life. FIRKO mice were healthy, lacked any of the metabolic abnormalities associated with lipodystrophy, and were protected against age-related deterioration in glucose tolerance, which was observed in all control strains. FIRKO mice maintained low body fat, despite normal food intake. Indeed, because FIRKO mice were leaner, the food intake of FIRKO mice expressed per gram of body weight actually exceeded that of controls by an average of 55%. Both male and female FIRKO mice were found to have an increase in mean life span of about 134 days (18%), with parallel increases in median and maximum life spans. Thus, Bluher et al. (2003) concluded that reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.
Song et al. (2003) found that in Drosophila, the insulin receptor functions in axon guidance and is required for photoreceptor cell axons to find their way from the retina to the brain during development of the visual system. The Drosophila insulin receptor functions as a guidance receptor for the adaptor protein Dock/Nck (see 600508). This function is independent of Chico, the Drosophila insulin receptor substrate homolog.
Nef et al. (2003) demonstrated that the insulin receptor tyrosine kinase family, comprising INSR, IGF1R (147370), and IRR (147671), is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry (480000) and the early testis-specific marker Sox9 (608160) indicated that the insulin signaling pathway is required for male sex determination.
Kondo et al. (2003) observed that, following relative hypoxia, mice with a vascular endothelial cell-specific Insr knockout (VENIRKO) showed a 57% decrease in retinal neovascularization compared to controls, which was associated with a blunted rise in the vascular mediators VEGF (192240), eNOS (NOS3; 163729), and endothelin-1 (EDN1; 131240). Mice with a vascular endothelial cell-specific knockout of the Igf1 receptor (VENIFARKO) showed only a 34% reduction in neovascularization and a very modest reduction in mediator generation. Kondo et al. (2003) concluded that both insulin and IGF1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with insulin having a greater effect.
By mosaic analysis of insulin receptor function in mice, Kitamura et al. (2004) demonstrated that insulin regulates growth independently of metabolism and that the number of insulin receptors is an important determinant of the specificity of insulin action. They generated mice with variable cellular mosaicism for null Insr alleles. Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles Donohue syndrome in humans (246200). Insr ablation in 98% of cells, although resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia. The growth retardation was associated with a greater than 60-fold increase in the expression of hepatic insulin-like growth factor-binding protein-1 (IGFBP1; 146730).
In mice, genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis (Accili et al., 1996). Okamoto et al. (2004) showed that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescued Insr knockout mice from neonatal death, prevented diabetes in a majority of animals, and normalized adipose tissue content, life span, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells were rescued from neonatal death, but developed lipoatrophic diabetes and died prematurely. Okamoto et al. (2004) concluded that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes.
Corl et al. (2005) found that specific inhibition of the insulin receptor or its signaling pathways in the nervous system led to increased ethanol sensitivity in Drosophila.
Ueki et al. (2006) created mice lacking both Insr and Igf1r only in pancreatic beta cells. These mice were born with the normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. At 2 weeks of age, normoglycemic beta cell-specific double-knockout mice showed reduced beta cell mass, reduced expression of phosphorylated Akt (164730) and the transcription factor MafA (610303), increased apoptosis in islets, and severely compromised beta cell function. Analyses of compound knockout showed a dominant role for insulin signaling in regulating beta cell mass. Ueki et al. (2006) concluded that insulin- and IGF1-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes.
Biddinger et al. (2008) generated liver-specific Insr-knockout mice (LIRKO) and observed a marked predisposition to cholesterol gallstone formation, with all of the LIRKO mice developing gallstones after 12 weeks on a lithogenic diet. This predisposition was due to at least 2 distinct mechanisms: disinhibition of the Foxo1 gene (136533), which increased expression of the biliary cholesterol transporters Abcg5 (605459) and Abcg8 (605460), resulting in an increase in biliary cholesterol secretion; and decreased expression of the bile acid synthetic enzymes, particularly Cyp7b1 (603711), which produced partial resistance to the farnesoid X receptor (NR1H4; 603826), leading to a lithogenic bile salt profile. Biddinger et al. (2008) concluded that hepatic insulin resistance provides the link between the metabolic syndrome (605552) and increased cholesterol gallstone susceptibility.
Rajala et al. (2008) generated rod photoreceptor-specific Insr-knockout mice and found that rods of mutant mice had reduced PI3K and Akt. Mutant mice had a normal phenotype when raised in dim light, but they exhibited significantly reduced retinal function and loss of photoreceptors when exposed to bright light. The authors proposed that INSR may be essential for photoreceptor neuroprotection.
Ardon et al. (2014) stated that this mutation is c.3104G-T in exon 17 and results in an amino acid change gly1035 to val (G1035V), according to a revised INSR sequence (GenBank NC_000019). Ardon et al. (2014) noted that this mutation has also been referred to as gly1008 to val (G1008V).
In a young Japanese male with insulin-resistant diabetes mellitus and acanthosis nigricans (610549), in whom impaired tyrosine protein kinase activity had been demonstrated, Odawara et al. (1989) cloned a cDNA for the insulin receptor. One of this person's alleles had a mutation in which valine was substituted for glycine-996 (GLY996VAL), the third glycine in the conserved gly-X-gly-X-X-gly motif in the putative binding site for adenosine triphosphate. Expression of the mutant receptor by transfection into Chinese hamster ovary cells confirmed that the mutation impairs tyrosine kinase activity. The presence of mutant receptors appeared to have negative effects on the activity of the normal receptor. Studies with kinase-deficient insulin receptors transfected into cultured cells show that such receptors function as dominant-negative mutations and suppress the function of endogenous insulin receptors (review by Kahn and Goldstein, 1989). In most other cases of insulin resistance, the mutation is expressed as a recessive. Yamamoto-Honda et al. (1990) studied the function of this mutant form of the insulin receptor.
Ardon et al. (2014) stated that this mutation is c.1459A-G in exon 6 and results in an amino acid change lys487 to glu (K487E), according to a revised INSR sequence (GenBank NC_000019).
Donohue syndrome (246200) is an autosomal recessive disorder due to a defect in the INSR gene. In the patient leprechaun/Ark-1, Kadowaki et al. (1988) found 2 different mutant alleles of the INSR gene. The patient was a compound heterozygote, with the maternal allele containing a missense mutation (AAG-to-GAG) encoding the substitution of glutamic acid for lysine at position 460 (LYS460GLU, K460E) in the alpha subunit and with the paternal allele having a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit (147670.0003), thereby deleting both the transmembrane and the tyrosine kinase domains of the receptor. The mutation was designated leprechaunism Ark-1/allele-1.
Ardon et al. (2014) stated that this mutation is c.2095C-T in exon 10 and results in an amino acid change gln699 to ter (Q699X), according to a revised INSR sequence (GenBank NC_000019).
In a case of Donohue syndrome (246200) due to compound heterozygosity for mutations in the INSR gene, Kadowaki et al. (1988) found that the paternal allele had a nonsense mutation (CAG-to-TAG) causing premature chain termination after amino acid 671 (GLN672TER, Q672X) in the alpha subunit, thereby deleting both the transmembrane and the tyrosine kinase domains of the receptor. This mutation was designated leprechaunism Ark-1 allele-2. The maternal allele carried a missense mutation (147670.0001).
Ardon et al. (2014) stated that this mutation is c.2286G-T in exon 12 and results in an amino acid change arg762 to ser (R762S), according to a revised INSR sequence (GenBank NC_000019).
Kakehi et al. (1988) found defective processing of the insulin receptor precursor in a 23-year-old Japanese female with extreme insulin resistance, acanthosis nigricans, bilateral polycystic ovaries, and decreased erythrocyte insulin binding (610549). Antireceptor antibodies showed the presence of increased amounts of a 210-kD protein but no detectable alpha or beta subunits. It appeared that the 190-kD receptor precursor was synthesized normally and underwent terminal glycosylation and normal intracellular transport to the cell surface, but that proteolytic maturation to alpha and beta subunits did not occur. The mutation could lie either in the INSR gene or in the gene for the receptor-processing enzyme. The former possibility proved to be correct. Yoshimasa et al. (1988) found that the insulin receptor gene in this patient had a point mutation within the tetrabasic processing site which was changed from arg-lys-arg-arg to arg-lys-arg-ser. Exon 12 contained a change in codon 735 from AGG-to-AGT (ARG735SER, R735S). Epstein-Barr virus-transformed lymphocytes from this patient synthesized an insulin receptor precursor that was normally glycosylated and inserted into the plasma membrane but was not cleaved to mature alpha and beta subunits. Insulin binding to these cells was severely reduced but could be increased about 5-fold by gentle treatment with trypsin, which was accompanied by appearance of normal alpha subunits. These results indicated that proteolysis of the proreceptor is necessary for its normal full insulin-binding sensitivity and signal-transducing activity and that a cellular protease that is more stringent in its specificity than trypsin is required to process the receptor precursor. The patient was a 23-year-old Japanese woman who was the product of a first-cousin marriage. Diabetes was first recognized at age 6. She showed nonketotic insulin-resistant diabetes mellitus with markedly elevated serum insulin values, acanthosis nigricans, hirsutism, and virilism. Her older sister was similarly affected. In addition, they showed some features not normally considered part of this syndrome, including mental retardation, short stature, and dental dysplasia. The latter 2 features have also been reported in an unrelated subject with Rabson-Mendenhall syndrome (Rabson and Mendenhall, 1956) who expressed an altered insulin receptor (Taylor et al., 1983). Insulin resistance due to this mutation behaved as a recessive.
Ardon et al. (2014) stated that this mutation is c.3680G-C in exon 21 and results in an amino acid change trp1227 to ser (W1227S), according to a revised INSR sequence (GenBank NC_000019).
In patient A(2) of the study of Grigorescu et al. (1986) with insulin-resistant diabetes and acanthosis nigricans (610549), Moller and Flier (1988) detected a heterozygous point mutation affecting the tyrosine kinase domain of the patient's insulin receptors, such that tryptophan-1200 was replaced by serine (TRP1200SER, W1200S). Hybridization of a mutant allele-specific oligonucleotide to PCR-amplified cDNA confirmed the presence of the mutant allele in the proband and excluded it in her unaffected sister and mother, 18 normal control subjects, and 6 other subjects with insulin resistance. Moller et al. (1990) showed that Chinese hamster ovary cells transfected with mutant cDNA produced a mutant receptor that was functionally severely impaired. The studies demonstrated the importance of trp-1200 to the normal function of the insulin receptor kinase. The observations demonstrated that severe insulin resistance can be caused by the heterozygous state of an INSR mutation. (Moller et al. (1990) used the nucleotide and amino acid numbering system of Ebina et al. (1985).)
Taira et al. (1989) studied a 17-year-old Japanese female who exhibited insulin-resistant diabetes, short stature, and acanthosis nigricans (610549). The mother had the same phenotype, whereas the father and 2 sibs were unaffected. The proband's maternal uncle and maternal grandfather were also said to be diabetic and of short stature. Erythrocytes and cultured fibroblasts from the proband and her mother had an insulin-binding capacity in the normal range, but cultured fibroblasts from both showed a below-normal rate of 2-deoxyglucose uptake. Therefore, the insulin resistance in this instance seemed to be due to a defect downstream from insulin binding. Taira et al. (1989) demonstrated that the mutant insulin receptor gene in these 2 subjects lacked almost the entire tyrosine kinase domain. Receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's lymphocytes that had been transformed by Epstein-Barr virus. With the use of several region-specific insulin receptor cDNA probes, Taira et al. (1989) analyzed the mutation further and demonstrated that it occurred at a nucleotide within the exon just before the codon for lys1030. This amino acid is part of the adenosine triphosphate (ATP)-binding site of the receptor and is required for tyrosine kinase activity. The exon containing the mutation corresponded to exon 17, which encodes the NH(2)-terminal part of the kinase domain. The sequence of the receptor gene was normal on the upstream side of the site of the mutation at nucleotide 145 (of the cloned fragment studied in detail); distal to this site it was entirely different to the point where a stop codon was reached at nucleotide 339. Thus, the putative product from the mutated gene has a new sequence of 65 amino acids at its COOH-terminus. The new sequence of the mutant allele was homologous to the consensus sequence of the Alu family, suggesting that the mutation resulted from recombination between exon 17 of the insulin receptor and an Alu sequence.
Ardon et al. (2014) cataloged this mutation as a complex rearrangement according to a revised INSR sequence (GenBank NC_000019).
Ardon et al. (2014) stated that this mutation is c.2770C-T in exon 14 and results in an amino acid change arg924 to ter (R924X), according to a revised INSR sequence (GenBank NC_000019).
In a patient with Donohue syndrome (246200), Kadowaki et al. (1990) identified a nonsense mutation at codon 897 (ARG897TER, R897X) in exon 14 in the paternal allele of the patient's insulin receptor gene. In addition, they obtained evidence that the patient's maternal allele contained a cis-acting dominant mutation that, like the paternal allele, caused a decrease in the level of mRNA. The nucleotide sequence of the entire protein-coding domain and the sequences of the intron-exon boundaries of all 22 exons of the maternal allele were normal. This mutation was designated leprechaunism Minn-1.
Ardon et al. (2014) stated that this mutation is c.3481G-A in exon 19 and results in an amino acid change ala1161 to thr (A1161T), according to a revised INSR sequence (GenBank NC_000019).
Moller et al. (1990) studied a family in which 3 sisters had the type A syndrome of insulin resistance (610549), the father was hyperinsulinemic without acanthosis nigricans or other abnormalities (see 125853), and the mother was normal. The daughters and father were found to be heterozygous for a single base substitution in codon 1134 (GCA to ACA, ala to thr; ALA1134THR, A1134T). Transfection of the mutant insulin receptor gene into CHO cells showed that the protein produced had markedly impaired insulin-stimulated autophosphorylation. The family demonstrates that severe insulin resistance with dominant inheritance can be caused by a missense mutation and can be clinically silent in a male. Moller et al. (1990) studied expression of the ala1134 mutant receptor in Chinese hamster ovary cells. The expressed mutant receptors were processed normally and displayed normal affinity in insulin binding but were markedly deficient in insulin-stimulated autophosphorylation. Moller et al. (1990) pointed out that alanine-1134 is a highly conserved residue located in a consensus sequence found in most tyrosine kinases.
Ardon et al. (2014) stated that this mutation is c.779T-C in exon 3 and results in an amino acid change leu260 to pro (L260P), according to a revised INSR sequence (GenBank NC_000019).
In a patient with Donohue syndrome (246200), the son of parents related as second cousins once removed, coming from the town of Geldeimalsen in the Netherlands, Klinkhamer et al. (1989) described a leucine-to-proline mutation at position 233 (LEU233PRO; L233P). By DNA amplification, they showed that the patient was homozygous and the parents and 2 of the grandparents from the consanguineous line were heterozygous. All the heterozygotes showed decreased insulin binding to cultured fibroblasts and had mild insulin resistance in vivo.
Ardon et al. (2014) stated that this mutation is c.1225T-G in exon 5 and results in an amino acid change phe409 to val (F409V), according to a revised INSR sequence (GenBank NC_000019).
In 2 women with insulin-resistant diabetes (see 125853), daughters of first-cousin, Venezuelan Caucasian parents, Accili et al. (1989) identified a T-to-G transversion at position 1273, leading to the substitution of valine for phenylalanine at position 382 in the alpha subunit of the insulin receptor (PHE382VAL; F382V). Inspection of mutant insulin receptor cDNA into NIH 3T3 cells demonstrated that the val382 mutation impaired posttranslational processing and retarded transport of the insulin receptor to the plasma membrane. They used multiple RFLPs to determine haplotypes at the INSR locus and arrived at a lod score of approximately 1.9 to 2.3 for linkage with insulin-resistant diabetes in this family. They pointed out that this lod score exceeds the threshold for declaring linkage when studying a single candidate locus (Lander and Botstein, 1987). The sisters had previously been reported by Barnes et al. (1974) as a case of insulin resistance possibly due to pineal gland dysfunction.
Ardon et al. (2014) stated that this mutation is c.126C-A in exon 2 and results in an amino acid change asn42 to lys (N42K), according to a revised INSR sequence (GenBank NC_000019).
Kadowaki et al. (1990) studied a patient (RM-1) with Rabson-Mendenhall syndrome (Moncada et al., 1986; 262190) who was found to be a compound heterozygote for 2 mutant alleles of the INSR gene: a missense mutation that substituted lysine for asparagine-15 (AAC to AAA; ASN15LYS, N15K) and a nonsense mutation at codon 1000 (CGA to TGA, ARG1000TER, R1000X; see 147670.0013). Kadowaki et al. (1990) characterized the lys15-mutant receptor expressed by transfection by mutant cDNA into NIH 3T3 cells. At least 2 defects in insulin receptor function were observed. The mutation retarded posttranslational processing of the receptor and impaired transport of the receptor to the plasma membrane, thereby reducing the number of the receptors on the cell surface. It also caused a 5-fold reduction in the affinity of the receptor for insulin. Kadowaki et al. (1990) suggested that both functional defects were related to distortion of the 3-dimensional structure of the receptor by the mutation. Presumably, the abnormal conformation interfered with the transport of the receptor through the endoplasmic reticulum and Golgi apparatus, and also inhibited the binding of insulin to its binding site.
Ardon et al. (2014) stated that this mutation is c.3079C-T in exon 17 and results in an amino acid change arg1027 to ter (R1027X), according to a revised INSR sequence (GenBank NC_000019).
See 147670.0012 and Kadowaki et al. (1990). See 147670.0018 and Kusari et al. (1991).
Ardon et al. (2014) stated that this mutation is c.707A-G in exon 3 and results in an amino acid change his236 to arg (H236R), according to a revised INSR sequence (GenBank NC_000019).
In a case of Donohue syndrome (246200) in a consanguineous Winnipeg pedigree, Kadowaki et al. (1990) found homozygosity for a CAC-to-CGC mutation resulting in substitution of histidine by arginine (HIS209ARG, H209R). Kadowaki et al. (1991) demonstrated that this mutation impairs receptor dimerization and transport of receptors to the cell surface. The small number of receptors that are transported to the cell surface bind insulin with normal affinity and have normal tyrosine kinase activity.
Ardon et al. (2014) stated that this mutation is c.479G-A in exon 2 and results in an amino acid change trp160 to ter (W160X), according to a revised INSR sequence (GenBank NC_000019).
In a patient (A-1) with insulin-resistant diabetes mellitus and acanthosis nigricans (610549), Kadowaki et al. (1990) found compound heterozygosity for a trp133 (TGG) nonsense mutation (TAG) (TRP133TER, W133X) and a missense mutation (AAT to AGT, ASN462SER, N462S; see 147670.0016).
Ardon et al. (2014) stated that this mutation is c.1466A-G in exon 6 and results in an amino acid change asn489 to ser (N489S), according to a revised INSR sequence (GenBank NC_000019).
See 147670.0015 and Kadowaki et al. (1990).
In a 16-year-old Japanese girl with type A insulin resistance (hyperinsulinemia, decreased insulin binding, and acanthosis nigricans; 610549), Shimada et al. (1990) found that 1 LDLR allele, inherited from her mother, contained a 1.2-kb deletion arising from a recombination between 2 Alu elements, one in intron 13 and the other in intron 14, and removing exon 14. The nature of the allele inherited from the father was not determined. The father had borderline impairment of glucose tolerance and mild insulin resistance. Shimada et al. (1992) extended these studies to demonstrate that the deletion shifted the reading frame, resulting in a termination codon after amino acid 867 (glu), thereby producing a truncated insulin receptor without a transmembrane region and cytoplasmic domain. They also sequenced all 22 exons of the INSR gene and found no mutation in exons except for the deletion of exon 14. Thus the patient was heterozygous for a single mutant allele.
Ardon et al. (2014) cataloged this mutation as a 1.2-kb deletion including exon 14 according to a revised INSR sequence (GenBank NC_000019).
Ardon et al. (2014) stated that this mutation is c.3059G-A in exon 17 and results in an amino acid change arg1020 to gln (R1020Q), according to a revised INSR sequence (GenBank NC_000019). According to Ardon et al. (2014), this mutation has also been known as arg993 to gln (R993Q).
In a patient with acanthosis and insulin-resistant diabetes (610549) described by Scarlett et al. (1982), Kusari et al. (1991) found compound heterozygosity at the INSR locus. The parents were not consanguineous. The paternal allele contained a missense mutation encoding the substitution of glutamine for arginine at position 981 (ARG981GLN, R981Q) in the tyrosine kinase domain of the receptor. The maternal allele contained a nonsense mutation causing premature termination after amino acid 988 in the beta subunit (ARG988TER, R988X; 147670.0013) thereby deleting most of the kinase domain. A CGA-to-CAA mutation was responsible for the first change, and a CGA-to-TGA mutation for the second.
Ardon et al. (2014) stated that this mutation is c.172G-A in exon 2 and results in an amino acid change gly58 to arg (G58R), according to a revised INSR sequence (GenBank NC_000019).
Maassen et al. (1988) described a patient named Helmond with Donohue syndrome (246200) in whom intact fibroblasts showed markedly reduced insulin binding but significant receptor autophosphorylation when the glycoprotein fraction was used. In this patient, van der Vorm et al. (1992) demonstrated a GGA-to-AGA change in exon 2 resulting in a gly31-to-arg substitution (GLY31ARG, G31R). The proband was a compound heterozygote. The mutation was present also in heterozygous state in the mother and maternal grandfather. In the mother and grandfather, the mutation was associated with decreased insulin binding to cultured fibroblasts and in vivo hyperinsulinemia after an oral glucose tolerance test. In the paternal line, all subjects had an insulin binding within the normal range and the G31R mutation was absent.
Ardon et al. (2014) stated that this mutation is c.3572G-A in exon 20 and results in an amino acid change arg1191 to gln (R1191Q), according to a revised INSR sequence (GenBank NC_000019). Ardon et al. (2014) noted that this mutation has also been classified as arg1164 to gln (R1164Q).
In a patient with noninsulin-dependent diabetes mellitus (125853), Cocozza et al. (1992) identified an abnormality in exon 20 of the INSR gene by denaturing gradient gel electrophoresis (DGGE). Sequencing showed heterozygosity for a change of codon 1152 from CGG to CAG, resulting in replacement of arginine with glutamine (ARG1152GLN, R1152Q). Although autophosphorylation of the purified insulin receptor seemed to be normal and the insulin binding to intact erythrocytes from the patient was in the normal range, the purified insulin receptor showed no detectable activity toward an exogenous substrate.
Esposito et al. (1995) screened a cohort of 68 Italian NIDDM patients and 65 controls for INSR R1152Q and did not find the variant in any patients or controls. The authors concluded that the R1152Q variant is not involved in the development of NIDDM in the Italian population.
Ardon et al. (2014) stated that this mutation is c.1195C-T in exon 5 and results in an amino acid change arg399 to ter (R399X), according to a revised INSR sequence (GenBank NC_000019).
In a black female, the second child of healthy unrelated parents of Hispanic and Afro-American descent, Longo et al. (1992) found the clinical features of Donohue syndrome (246200) related to compound heterozygosity for different mutations. The paternally derived mutation, a C-to-T transition at bp 1333, converted arginine-372 to a stop codon (ARG372TER, R372X). The maternally inherited allele had no mutations within the protein-coding region, suggesting that the second mutation was located in a region of the INSR gene involving control of gene expression. The clinical features of the patient were reported by Norton et al. (1990). The mutation was labeled leprechaunism Mount Sinai.
Ardon et al. (2014) stated that this mutation is c.164T-C in exon 2 and results in an amino acid change val55 to ala (V55A), according to a revised INSR sequence (GenBank NC_000019).
Barbetti et al. (1992) used denaturing gradient gel electrophoresis (DGGE) to identify compound heterozygosity for 2 different mutations in the INSR gene in a patient labeled leprechaun/Verona-1. The patient was a white female whose appearance suggested Donohue syndrome (246200) at birth (characteristic facies, hirsutism, clitoromegaly). Immediately after birth, she developed hypoglycemia during fasting. In addition, she became hyperglycemic after meals. Her peak immunoreactive insulin during an oral glucose tolerance test was very high. At age 6.5 years, pelvic sonogram demonstrated polycystic ovaries, and abdominal sonogram showed bilateral medullary sponge kidneys. The INSR allele inherited from the father had a mutation substituting alanine for valine-28 (VAL28ALA, V28A); in the allele inherited from the mother, arginine was substituted for glycine-366 (GLY366ARG, G366R). Barbetti et al. (1992) applied the DGGE method also to several other cases of Donohue syndrome in whom the genetic defect had previously been identified.
Ardon et al. (2014) stated that this mutation is c.1177G-A in exon 5 and results in an amino acid change gly393 to arg (G393R), according to a revised INSR sequence (GenBank NC_000019).
See 147670.0023.
Ardon et al. (2014) stated that this mutation is c.338G-C in exon 2 and results in an amino acid change arg113 to pro (R113P), according to a revised INSR sequence (GenBank NC_000019).
Fibroblasts cultured from a patient with Donohue syndrome (246200) with intrauterine growth retardation and severe insulin resistance (designated leprechaun Atlanta (Atl)-1) had normal amounts of insulin receptor protein and defective insulin binding but constitutive activation of insulin-receptor autophosphorylation and kinase activity and of glucose transport (Longo et al., 1993). In the same fibroblasts, growth was impaired. Homozygosity for a mutation in the INSR gene was suspected, since he inherited identical DNA haplotypes for this gene from the parents who were blood relatives. Longo et al. (1993) found that indeed the proband was homozygous and both parents were heterozygous for a G-to-C transversion at nucleotide 476 of the INSR cDNA converting arginine-86 to proline (ARG86PRO, R86P). Expression of this mutation in CHO cells duplicated the natural mutation by activating glucose transport without increasing insulin binding or insulin-stimulated cellular growth. The R86P substitution is contiguous to the hydrophobic beta-sheet of the receptor alpha subunit implicated in the binding of aromatic residues of the insulin molecule.
Ardon et al. (2014) stated that this mutation is c.3485C-A in exon 19 and results in an amino acid change ala1162 to glu (A1162E), according to a revised INSR sequence (GenBank NC_000019).
Cama et al. (1993) described the molecular findings in a 32-year-old woman with insulin resistance. She had presented to medical attention at the age of 11 with features of type A insulin resistance including acanthosis nigricans and virilization (610549). Subsequently, her acanthosis nigricans disappeared and she began to ovulate spontaneously, became pregnant without medical intervention, and had an apparently normal daughter. Using oligonucleotides complementary to sequences in introns 18 and 19, Cama et al. (1993) used PCR to amplify exon 19 of the insulin receptor gene. By direct sequencing of the amplified genomic DNA, they demonstrated that codon 1135 was mutated from GCG (ala) to GAG (glu) (ALA1135GLU, A1135E). Neither parent had the mutation, which was heterozygous in the proposita. Like previously described mutations in the tyrosine kinase domain, the glu1135 mutation impaired receptor tyrosine kinase activity and inhibited the ability of insulin to stimulate thymidine incorporation and receptor endocytosis. However, unlike previously described mutations in the intracellular domain of the receptor, the new mutation impaired proteolytic cleavage of the proreceptor into separate subunits and impaired the transport of the receptor to the cell surface. The latter defect accounted for the decrease in number of receptors on the cell surface of the patient's circulating monocytes.
Ardon et al. (2014) stated that this mutation is c.442A-T in exon 2 and results in an amino acid change lys148 to ter (K148X), according to a revised INSR sequence (GenBank NC_000019).
In an offspring of consanguineous parents of Pakistani origin, Krook et al. (1993) observed Donohue syndrome (246200) resulting from homozygosity for a nonsense mutation, lys121 to ter (LYS121TER, K121X). Severe intrauterine growth retardation had been evident throughout pregnancy and at birth the baby had a wasted appearance with a distended abdomen, lack of subcutaneous fat, and decreased muscle mass. The facies was gaunt with pronounced hirsutism, protuberant ears, and gum hypertrophy. There was generalized hypertrichosis. Both parents were heterozygous for a mutation in codon 121 of the INSR gene that changed AAG (lysine) to TAG (stop).
Ardon et al. (2014) cataloged this mutation as a deletion of the entire INSR gene according to a revised INSR sequence (GenBank NC_000019).
In a 15-month-old boy with Donohue syndrome (246200), an offspring of first-cousin parents, Wertheimer et al. (1993) found homozygous deletion of the INSR gene. Thus, contrary to previous predictions, complete absence of the INSR gene is compatible with life.
This variant, formerly titled DIABETES MELLITUS, NONINSULIN-DEPENDENT, has been reclassified based on the report of Lek et al. (2016).
Ardon et al. (2014) stated that this mutation is c.3034G-A in exon 17 and results in an amino acid change val1012 to met (V1012M), according to a revised INSR sequence (GenBank NC_000019).
In studies of 11 familial NIDDM pedigrees (125853), Elbein et al. (1993) found 1 in which some members had a val985-to-met substitution in exon 17 (VAL985MET, V985M). The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was absent in 1 affected individual and was present in some nondiabetic pedigree members. Nondiabetic carriers of the mutation were found to have significantly higher glucose levels when compared with 266 members of other pedigrees, after correction for age, weight, and sex. Elbein et al. (1993) suggested that although the val985-to-met substitution does not result in severe insulin resistance and has low penetrance with respect to expression of the NIDDM phenotype, it may represent a modifying factor collaborating with other loci predisposing to diabetes.
In a population-based Rotterdam study, 't Hart et al. (1996) examined 161 individuals with NIDDM and 538 healthy controls for the presence of mutations in the INSR gene, using SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, the findings indicated a relative risk for diabetes of 4.49 for met985 carriers. When the total study group was analyzed, 't Hart et al. (1996) found that the prevalence of the mutation increased with increasing serum glucose levels.
In a study of random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies, 't Hart et al. (1999) found the val985-to-met INSR variant at frequencies of 4.4 and 1.8%, respectively, in NIDDM and normoglycemic patients. Inclusion of data from 2 other studies yielded a summarized odds ratio of 1.87. The authors concluded that the association between the val985-to-met variant in the INSR gene and type II diabetes, previously reported in the Rotterdam study, is supported by the joint analysis with a second population-based study and other studies.
Lek et al. (2016) noted that the V1012M variant has a high allele frequency (0.0225) in the South Asian population in the ExAC database, suggesting that it is not pathogenic.
Ardon et al. (2014) stated that this mutation is c.3602G-A in exon 20 and results in an amino acid change arg1201 to gln (R1201Q), according to a revised INSR sequence (GenBank NC_000019).
Among 22 unrelated women with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (manifested by hyperandrogenemia, oligoamenorrhea, and hirsutism; 610549), Moller et al. (1994) found heterozygosity for a CGG-to-CAG transition in exon 20 of the INSR gene, resulting in an arg1174-to-gln (ARG1174GLN, R1174Q) amino acid substitution. The mutation involved the intracellular receptor beta subunit. The mutation was found in an affected sister, whereas it was absent in the unaffected mother. It was probably present in 2 paternal aunts who were reportedly affected. Thus, arg1174 to gln, involving the insulin receptor tyrosine kinase domain, is a cause of dominantly inherited insulin resistance.
In all affected members of a 3-generation Danish family with hyperinsulinemic hypoglycemia (609968), Hojlund et al. (2004) identified heterozygosity for a G-A transition at codon 1174 in exon 20 of the INSR gene, resulting in an arg1174-to-gln (R1174Q) substitution. The mutation was not found in any unaffected family members.
Ardon et al. (2014) stated that this mutation is c.3540G-A in exon 20 and results in an amino acid change met1180 to ile (M1180I), according to a revised INSR sequence (GenBank NC_000019).
A met1153-to-ile mutation (MET1153ILE, M1153I) in the INSR gene was demonstrated to be the cause of insulin resistance by Cama et al. (1991, 1992). The mutation caused a defect in receptor internalization relative to normal receptors. Insulin resistance in the patient showed a fluctuating clinical course, suggesting that the ratio of normal receptors to mutant receptors on the surface of the patient's cells may change depending on factors that promote or inhibit receptor endocytosis, such as hyperinsulinemia and obesity. Quon et al. (1994) applied to the study of this mutation a physiologically relevant system for dissecting the molecular mechanisms of insulin signal transduction related to glucose transport. The method involved transfection of DNA into rat adipose cells in primary culture. As a reporter gene, they used cDNA coding for GLUT4 (138190) with an epitope tag in the first exofacial loop so that GLUT4 translocation could be studied exclusively in transfected cells. Insulin stimulated a 4.3-fold recruitment of transfected epitope-tagged GLUT4 to the cell surface. Cells cotransfected with the reporter gene and the human insulin receptor gene showed an increase in cell surface GLUT4 in the basal state (no insulin) to levels comparable to those seen with maximal insulin stimulation of cells transfected with the reporter gene alone. In contrast, cells overexpressing the met1153-to-ile mutation showed no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. In contrast, cells overexpressing the met1163-to-ile mutation showed no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. The results were interpreted as indicating that insulin receptor tyrosine kinase activity is essential in insulin-stimulated glucose transport in adipose cells.
Ardon et al. (2014) stated that this mutation is c.1316G-C in exon 6 and results in an amino acid change trp439 to ser (W439S), according to a revised INSR sequence (GenBank NC_000019).
In a child with Donohue syndrome (246200), the offspring of consanguineous Turkish parents, van der Vorm et al. (1994) found a trp412-to-ser mutation (TRP412SER, W412S) in the INSR gene. The mutant receptor was expressed stably in CHO cells and transiently in COS-1 cells where it was found that the mutant was not cleaved into alpha- and beta-subunits but remained as a 210-kD proreceptor at an intracellular site. Cross-linking experiments showed that the mutant proreceptor was able to bind insulin with an affinity comparable to that of the wildtype alpha chain. Despite its capacity to bind insulin, the mutant receptor was not autophosphorylated. Impaired transport of the proreceptor to the cell surface appeared to be the primary cause for the binding defect observed in intact cells. The patient was thought to be homozygous for the mutation.
Ardon et al. (2014) stated that this mutation is c.438C-G in exon 2 and results in an amino acid change ile146 to met (I146M), according to a revised INSR sequence (GenBank NC_000019).
Al-Gazali et al. (1993) described a 'mild' variant of Donohue syndrome (246200) in 5 infants from an inbred family. Using denaturing gradient gel electrophoresis and subsequent sequence of selected exons, Hone et al. (1994) identified a homozygous mutation resulting from an ile119-to-met (ILE119MET, I119M) substitution in exon 2 of the INSR gene in this family. Mutation in the insulin binding domain predicts ineffective insulin signal transduction.
Ardon et al. (2014) cataloged this mutation as c.1124-2A-G according to a revised INSR sequence (GenBank NC_000019).
In an English patient with Rabson-Mendenhall syndrome (262190), Takahashi et al. (1998) found compound heterozygosity for novel mutations in the INSR gene. One was an A-to-G transition at the 3-prime splice acceptor site of intron 4, and the other was an 8-bp deletion in exon 12. Both decreased mRNA expression in a cis-dominant manner, and were predicted to produce severely truncated proteins. Unexpectedly, nearly normal insulin receptor levels were expressed in the patient's lymphocytes, although the level of expression assessed by immunoblot was approximately 10% of the control cells. Insulin-binding affinity was markedly reduced, but insulin-dependent tyrosine kinase activity was present. On analysis of INSR mRNA of lymphocytes by RT-PCR, aberrant splicing caused by activation of a cryptic splice site in exon 5, resulting in a 4-amino acid deletion and 1-amino acid substitution, but restoring an open reading frame, was found. Skipped exon 5, another aberrant splicing, was found in both the patient and the mother who was heterozygous for the mutation, whereas activation of the cryptic splice site occurred almost exclusively in the patient. Takahashi et al. (1998) speculated that the mutant receptor may have been involved in the relatively long survival of the patient by rescuing an otherwise more severe phenotype resulting from the complete lack of functional insulin receptors. The patient, previously reported by Quin et al. (1990), had severe insulin-resistant diabetes and intermittent ketonuria, and was treated successfully with recombinant insulinlike growth factor 1 (IGF1; 147440). Although other therapeutic agents were unsuccessful, the patient lived to age 13, when he began subcutaneous IGF1 injections.
Ardon et al. (2014) cataloged this mutation as c.2480_2487del8 in exon 12 according to a revised INSR sequence (GenBank NC_000019).
See 147670.0034 and Takahashi et al. (1998).
Ardon et al. (2014) stated that this mutation is c.1372A-G in exon 6 and results in an amino acid change asn458 to asp (N458D), according to a revised INSR sequence (GenBank NC_000019).
In a Scottish Caucasian male with Donohue syndrome (246200) who died at 3 months of age, Maassen et al. (2003) detected a novel homozygous A-to-G transition in the INSR gene that resulted in an asn431-to-asp (ASN431ASP, N431D) amino acid change. The N431D mutation only partially reduced insulin proreceptor processing and activation of signaling cascades. The correlation between fibroblast insulin binding and duration of patient survival reported by Longo et al. (2002) was not observed.
't Hart, L. M., Stolk, R. P., Dekker, J. M., Nijpels, G., Grobbee, D. E., Heine, R. J., Maassen, J. A. Prevalence of variants in candidate genes for type 2 diabetes mellitus in the Netherlands: the Rotterdam study and the Hoorn study. J. Clin. Endocr. Metab. 84: 1002-1006, 1999. [PubMed: 10084586] [Full Text: https://doi.org/10.1210/jcem.84.3.5563]
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