IRS2 variants and syndromes of severe insulin resistance

Bottomley, William; Soos, Maria A.; Adams, Claire A.; Güran, Tülay; Howlett, Trevor A.; Mackie, Anna; Miell, John P.; Monson, John P.; Temple, Rosemary; Tenenbaum‐Rakover, Yardena; Tymms, James; Savage, David B.; Semple, Robert K.; O’Rahilly, Stephen; Barroso, Inês

doi:10.1007/s00125-009-1345-4

Cited by 8 publications

(8 citation statements)

References 9 publications

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“…Two in-frame insertion mutations in IRS-2, one germline (p.Ala701_Val702insAla) and the other tumor-associated (p.Asn28_His29insAsn), were identified in CRC cases. These genetic variants were not detected in the control subjects of this study and in previous mutational analyses (17,28–30) and are not described in public databases. Overall, nearly 17% of the CRC tested (cell lines and primary CRC cases) had unique missense or a deletion or insertion mutations in IRS-1 and/or IRS-2.…”

Section: Resultsmentioning

confidence: 50%

“…Table IV summarizes the frequencies of 6 allelic variants identified in IRS-2 (c.2169C>T, c.2448T>C, c.2487C>T, p.Gly879Ser, pGly882Ala and p.Gly1057Asp), that were also detected in the general population (17,28–30) and are described in public databases.…”

Section: Resultsmentioning

confidence: 99%

“…Tables VI and VII summarize the 18 distinct allelic variants identified in IRS-2. Some of the detected IRS-1 and IRS-2 variants are common polymorphisms also found in the general population (Table VII) (17,20–30) and are described in public databases.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of IRS-2, the control sequences included those obtained by Bottomley et al (17) in 173 normal subjects. Furthermore, we performed IRS-2 mutational analysis in 25 control subjects (50 alleles), and the screening was extended to more alleles for some variants.…”

Section: Methodsmentioning

confidence: 99%

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Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

et al. 2013

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The insulin/insulin-like growth factor pathway is involved in breast and colorectal cancer (CRC) development. In the present study, we analyzed the coding region and short intron-exon borders of the insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) genes in 12 cell lines derived from breast cancer (BC), 14 cell lines derived from CRC and 33 primary CRCs. The nucleotide variants identified in BC were 3 in IRS-1, 1 of which (p.Arg267Cys) was novel and with a pathogenic potential as predicted by in silico analysis and 6 in IRS-2. Twenty-one variants in IRS-1 and 18 in IRS-2 were identified in the CRC samples. These included 11 novel IRS-1 variants detected exclusively in CRCs, which included 5 missense (p.Pro559Leu, p.Gln655His, p.Asp1014Gly, p.Asp1181His and pPro1203Ser) with a pathogenic potential as predicted by in silico analysis, 2 frameshifts predicted to generate a truncated protein, 1 splice-site mutation and 3 silent variants. In the CRC samples we also identified 7 novel IRS-2 variants, including 4 missense variants, which included 2 (p.Asp782Asn and p.Gly1230Ser) with a pathogenic potential as predicted by in silico analysis, 2 frame insertion mutations and 1 silent variant. Most of the novel IRS-1 and IRS-2 variants may be involved in the modulation of IRS-1 or IRS-2 functions and could be relevant to breast and colorectal tumorigenesis.

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Section: Resultsmentioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

et al. 2013

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“…In French Caucasian women, SNP (codon 1057) was associated with severe obesity (22). Bottomley et al (9) sequenced the coding region of IRS2 in 161 European nonobese and obese adults with severe insulin resistance. Eight rare, nonsynonymous variants were identified, but there was no clear evidence that these variants had a pathogenic effect on insulin resistance.…”

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confidence: 99%

Resequencing ofIRS2reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children

Butte

Voruganti

Cole

et al. 2011

Physiological Genomics

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Butte NF, Voruganti VS, Cole SA, Haack K, Comuzzie AG, Muzny DM, Wheeler DA, Chang K, Hawes A, Gibbs RA. Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children. Physiol Genomics 43: 1029-1037, 2011. First published July 19, 2011 doi:10.1152/physiolgenomics.00019.2011Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity-and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5= and 3= flanking regions of IRS2 (ϳ14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3=-UTR, and 2 in the 5=-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF ϭ 0.001-0.009) were associated with obesity-related traits (P ϭ 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P ϭ 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children. DNA resequencing; diabetes; body mass index; single nucleotide polymorphisms; indels; insulin receptor substrate 2 INSULIN RECEPTOR SUBSTRATE 2 (IRS2) is a compelling candidate gene for obesity, insulin resistance, and Type 2 diabetes given its role in insulin signal transduction and the manifestation of obesity, insulin resistance and ␤-cell failure in Irs2Ϫ/Ϫ mice (30), and yet human studies of common IRS2 variants have not demonstrated consistent effects (2)(3)(4)34). IRS2 is a cytoplasmic signaling protein that mediates effects of insulin, insulinlike growth factor-1, and cytokines by acting as a relay protein between diverse receptor tyrosine kinases and downstream effectors (35,36) and thereby accounting for the diverse actions of insulin (18). Structurally, IRS2 has many modified residues (phosphotyrosines, phosphoserines, and phosphothreonines) and a CpG island in the promoter region, which suggests high regulatory potential. Highly express...

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Influence of the Gly1057Asp variant of the insulin receptor substrate 2 (IRS2) on insulin resistance and relationship with epicardial fat thickness in the elderly

Mazzoccoli

Dagostino

Fontana

et al. 2012

Experimental Gerontology

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IRS2 variants and syndromes of severe insulin resistance

Cited by 8 publications

References 9 publications

Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

Resequencing ofIRS2reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children

Influence of the Gly1057Asp variant of the insulin receptor substrate 2 (IRS2) on insulin resistance and relationship with epicardial fat thickness in the elderly

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