A Nonsense Mutation in the Arg345 of the Insulin Receptor Gene in a Japanese Type A Insulin-resistant Patient

Hashiramoto, Mitsuru; Osawa, Haruhiko; Ando, Mitsuhiro; Murakami, Akiko; Nishimiya, Tatsuya; Nakano, Masao; Nishida, Wataru; Onuma, Hiroshi; Makino, Hideichi

doi:10.1507/endocrj.52.499

Cited by 7 publications

(4 citation statements)

References 29 publications

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“…At 19p13.3, rs2059807 is located in the intron of the INSR (insulin receptor) gene and in previous studies, common SNPs in the INSR gene have been reported to be associated with PCOS in both Han Chinese individuals and those of European ancestry. INSR has an important role in insulin metabolism, consistent with a very common explanation for the pathogenesis of PCOS, namely, insulin resistance (8). Mutations affecting the tyrosine kinase domain of the insulin receptor are known to cause severe hyperinsulinemia and insulin resistance (9).…”

Section: Introductionmentioning

confidence: 55%

Association between Common Genetic Variants and Polycystic Ovary Syndrome Risk in a Chinese Han Population

Sun¹,

Yuan²,

Yang³

et al. 2016

Jcrpe

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Objective:Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women worldwide. The aim of our study was to explore the PCOS-related single nucleotide polymorphism (SNP) associations between common genetic variants and PCOS risk in a Han Chinese women population.Methods:In this case-control study, 285 Chinese Han women aged 28.50±6.858 years with PCOS and 299 controls of a mean age of 32.66±7.018 years were compared. We selected recently published genome-wide association studies (GWAS) which identified several genetic loci in PCOS. All the SNPs were genotyped by Sequenom Mass-ARRAY technology. Associations between the gene and the risk of PCOS were tested using various genetic models by Statistical Package for the Social Sciences and Plink.Results:We found that rs705702 in the RAB5B/SUOX was associated with PCOS (odds ratio=1.42; 95% confidence interval=1.08-1.87, p=0.011) and increased the PCOS risk. The genotypic model analysis also showed that rs705702 was associated with PCOS risk.Conclusion:Our results suggest that SNPs rs705702 in gene RAB5B/SUOX was associated with PCOS in Han Chinese women.

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Section: Introductionmentioning

confidence: 55%

Association between Common Genetic Variants and Polycystic Ovary Syndrome Risk in a Chinese Han Population

Sun¹,

Yuan²,

Yang³

et al. 2016

Jcrpe

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“…There are several mutations in the INSR, which have been classified into several classes: class1 (impaired receptor biosynthesis); class II (receptors with impaired processing and trafficking to plasma membrane); class III (decreased affinity to insulin binding); class IV (receptors with defective phosphorylation and kinase activity); and class V (receptor recycling defects and receptor degradation in lysosome) [61]. There are two types of INSR mutations, autosomal recessive and mild type mutations.…”

Section: Mutations In Insr and Insulin Signaling Genesmentioning

confidence: 99%

Insulin Resistance in Diabetes: The Promise of Using Induced Pluripotent Stem Cell Technology

Elsayed

Vimalraj

Nandakumar

et al. 2020

Preprint

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In this review, we discuss the insulin resistance (IR) and its development in the insulin target tissues that leads to diabetes. Also, we highlight the use of induced pluripotent stem cells (iPSCs) to understand the mechanisms underlying the development of IR. IR is associated with several metabolic disorders, including type 2 diabetes (T2D). The development of IR in insulin target tissues involves genetic and acquired factors. Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance. Although there are currently several mouse models for both IR and T2D that had provided a lot of information about the disease, these models cannot recapitulate all the aspects of this complex disease as seen in each individual. Patient-specific iPSCs can overcome the hurdles faced with the classical mouse models for studying IR. iPSC technology can generate cells genetically identical to IR individuals, which can help in distinguishing between genetic and acquired defects in insulin sensitivity. Combining the technologies of the genome editing and iPSCs may provide important information about the inherited factors underlying the development of different forms of IR. Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.

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“…2,[5][6][7] Mutations in the INSR gene are the most common cause of monogenic insulin resistance, and more than 90 different mutations have been identified so far in patients with type A insulin resistance, Rabson-Mendenhall syndrome or Donohue syndrome (leprechaunism). 2,[8][9][10][11][12][13] The clinical spectrum of these inherited disorders reflects the severity of dysfunctional receptor, 12 ranging from mild type A insulin resistance to the most severe form of the disease, Donohue syndrome, which is characterized by excessive hyperglycaemia with hyperinsulinism, pre-and postnatal growth retardation, distinct dysmorphism, acanthosis nigricans and death in the first 2 years of life. Patients with Rabson-Mendenhall syndrome have a less severe phenotype but seldom survive through childhood owing to b-cell failure and severe diabetic ketoacidosis.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, inherited severe insulin resistance is frequently associated with rare monogenic disorders and usually results from mutations in the insulin signalling pathway 2,5–7 . Mutations in the INSR gene are the most common cause of monogenic insulin resistance, and more than 90 different mutations have been identified so far in patients with type A insulin resistance, Rabson–Mendenhall syndrome or Donohue syndrome (leprechaunism) 2,8–13 . The clinical spectrum of these inherited disorders reflects the severity of dysfunctional receptor, 12 ranging from mild type A insulin resistance to the most severe form of the disease, Donohue syndrome, which is characterized by excessive hyperglycaemia with hyperinsulinism, pre‐ and postnatal growth retardation, distinct dysmorphism, acanthosis nigricans and death in the first 2 years of life.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of a novel p.R118C mutation in the insulin receptor gene from patients with severe insulin resistance

Alzahrani

Zou²,

Baitei³

et al. 2012

Clinical Endocrinology

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Summary Context Mutations of the insulin receptor gene (INSR) can cause genetic syndromes associated with severe insulin resistance. Objectives We aimed to analyse INSR mutations in Saudi patients with severe insulin resistance. Design Ten patients with Type A insulin resistance syndrome from five unrelated Saudi families were investigated. The entire coding region of INSR was sequenced. The founder effect was assessed by microsatellite haplotype analysis. The functional effect of the mutation was investigated by in vitro functional assays. Results A novel biallelic c.433 C>T (p.R118C) mutation was detected in all patients. The c.433 C>T (p.R118C) sequence variation was not found in 100 population controls. The arginine residue at position 118 is located in the ligand‐binding domain of INSR and is highly conserved across species. Microsatellite haplotype analysis of these patients indicated that p.R118C was a founder mutation created approximately 2900 years ago. The wild‐type and mutant R118C INSR were cloned and expressed in CHO cells for functional analysis. Specific insulin binding to the mutant receptor was reduced by 83% as compared to wild‐type (WT), although the mutant receptor was processed and expressed on the cell surface. Insulin‐mediated receptor autophosphorylation was also significantly reduced in CHOR118C cells. Conclusions Biallelic c.433 C>T (p.R118C) mutation of INSR causes significant damage to insulin binding and insulin‐mediated signal transduction. p.R118C is a founder mutation frequently present in the Saudi patients with severe insulin resistance.

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A Nonsense Mutation in the Arg345 of the Insulin Receptor Gene in a Japanese Type A Insulin-resistant Patient

Cited by 7 publications

References 29 publications

Association between Common Genetic Variants and Polycystic Ovary Syndrome Risk in a Chinese Han Population

Association between Common Genetic Variants and Polycystic Ovary Syndrome Risk in a Chinese Han Population

Insulin Resistance in Diabetes: The Promise of Using Induced Pluripotent Stem Cell Technology

Molecular characterization of a novel p.R118C mutation in the insulin receptor gene from patients with severe insulin resistance

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