Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome
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Ángela Domínguez-García
Abstract
Background: Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of insulin resistance.
Patient report: We describe a 12-year-old girl with type A insulin resistance with hyperandrogenism, hyperinsulinemia, and diabetes mellitus but without the dysmorphic characteristic of leprechaunism or Rabson-Mendenhall syndrome. The proband’s mother had hyperinsulinemia and diabetes mellitus but did not show any common clinical features of type A insulin resistance. The proband’s brother also had hyperinsulinemia but manifested neither glucose intolerance nor common clinical features of type A insulin resistance. A novel heterozygous mutation, p.Asn1164Thr, of the insulin receptor gene (INSR) was identified in this family.
Conclusion: These cases illustrate the diversity of clinical phenotypes associated with mutations of the insulin receptor gene.
Acknowledgments
This work was partially funded by Research Project grants from the Instituto de Salud Carlos III of the Spanish Ministry of Health (PS09/01492), from the Basque Departments of Health (GV2010111185), and from the University of Basque Country (IT-472-07).
Conflict of interest statement
Competing interests: None declared.
References
1. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995;16:117–42.Search in Google Scholar
2. Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 2002;11:1465–75.10.1093/hmg/11.12.1465Search in Google Scholar PubMed
3. Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ, et al. Mutations in the insulin receptor gene. Endocr Rev 1992;13:566–95.10.1210/edrv-13-3-566Search in Google Scholar PubMed
4. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, et al. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med 1976;294:739–45.10.1056/NEJM197604012941401Search in Google Scholar PubMed
5. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005;16:465–72.10.1097/00019501-200512000-00002Search in Google Scholar PubMed
6. Mantzoros CS, Flier JS. Insulin resistance: the clinical spectrum. In: Mazzaferi E, editor. Advances in endocrinology and metabolism. vol. 6. St. Louis: Mosby-Year Book, 1995:193–232.Search in Google Scholar
7. Vidal-Puig A, Moller DE. Insulin resistance: classification, prevalence, clinical manifestations, and diagnosis. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in women. Philadelphia: Lippincott Raven, 1997:227–36.Search in Google Scholar
8. Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev 2011;32:498–514.10.1210/er.2010-0020Search in Google Scholar PubMed
9. Ten S, Maclaren N. Insulin resistance syndrome in children. J Clin Endocrinol 2004;89:2526–9.10.1210/jc.2004-0276Search in Google Scholar PubMed
10. Takahashi I, Yamada Y, Kadowaki H, Horikoshi M, Kadowaki T, et al. Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene. Endocrine J 2010;57:509–16.10.1507/endocrj.K09E-339Search in Google Scholar PubMed
11. Huang Z, Li Y, Tang T, Xu W, Liao Z, et al. Hyperinsulinemaemic hypoglycaemia associated with a heterozygous missense mutation of R1174W the insulin receptor gene. Clin Endocrinol J 2009;71:659–65.10.1111/j.1365-2265.2009.03525.xSearch in Google Scholar PubMed
12. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 2004;83:209–22.10.1097/01.md.0000133625.73570.54Search in Google Scholar PubMed
13. Hashiramoto M, Osawa H, Ando M, Murakami A, Nishimiya T, et al. A nonsense mutation in the Arg345 of the insulin receptor gene in a Japanese type A insulin-resistant patient. Endocr J 2005;52:499–504.10.1507/endocrj.52.499Search in Google Scholar PubMed
14. Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, et al. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 1990;86:254–64.10.1172/JCI114693Search in Google Scholar
15. Ogawa W, Iwamoto K, Mori H, Hashiramoto M, Miyake K, et al. Two related cases of type A insulin resistance with compound heterozygous mutations of the insulin receptor gene. Diabetes Res Clin Pract 2009;83:e75–7.10.1016/j.diabres.2008.12.002Search in Google Scholar
16. Maassen JA, Tobias ES, Kayserilli H, Tukel T, Yuksel-Apak M, et al. Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance. J Clin Endocrinol Metab 2003;88:4251–7.10.1210/jc.2003-030034Search in Google Scholar
17. Moller DE, Cohen O, Yamaguchi Y, Assiz R, Grigorescu F, et al. Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance. Diabetes 1994;43:247–55.10.2337/diab.43.2.247Search in Google Scholar
18. Iwanishi M, Haruta T, Takata Y, Ishibashi O, Sasaoka T, et al. A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance. Diabetologia 1993;36:414–22.10.1007/BF00402277Search in Google Scholar
19. Takahashi Y, Kadowaki H, Momomura K, Fukushima Y, Orban T, et al. A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism. Diabetologia 1997;40:412–20.10.1007/s001250050695Search in Google Scholar
20. Moller DE, Yokota A, White MF, Pazianos AG, Flier JS. A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. J Biol Chem 1990;265:14979–85.10.1016/S0021-9258(18)77212-8Search in Google Scholar
©2014 by Walter de Gruyter Berlin/Boston
Articles in the same Issue
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- Increased hunger and speed of eating in obese children and adolescents
- Glucagon and insulin cord blood levels in very preterm, late preterm and full-term infants
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- Asymmetric dimethyl L-arginine, nitric oxide and cardiovascular disease in adolescent type 1 diabetics
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Articles in the same Issue
- Frontmatter
- Original articles
- Assessment of hearing in children with type 1 diabetes mellitus
- Insulin resistance and lipid profiles in HIV-infected Thai children receiving lopinavir/ritonavir-based highly active antiretroviral therapy
- Increased hunger and speed of eating in obese children and adolescents
- Glucagon and insulin cord blood levels in very preterm, late preterm and full-term infants
- Thyroid function in late preterm infants in relation to mode of delivery and respiratory support
- Prevalence of vitamin D deficiency and its related factors in children and adolescents living in North Khorasan, Iran
- Asymmetric dimethyl L-arginine, nitric oxide and cardiovascular disease in adolescent type 1 diabetics
- A combined nutritional-behavioral-physical activity intervention for the treatment of childhood obesity – a 7-year summary
- The effect of earlier puberty on cardiometabolic risk factors in Afro-Caribbean children
- Prevalence of risk of deficiency and inadequacy of 25-hydroxyvitamin D in US children: NHANES 2003–2006
- Serum uric acid: relationships with biomarkers in adolescents and changes over 1 year
- Psychological impact on parents of children with congenital adrenal hyperplasia: a study from Sri Lanka
- Investigation of adropin and leptin levels in pediatric obesity-related nonalcoholic fatty liver disease
- Diseases accompanying congenital hypothyroidism
- Molecular diagnosis of a Chinese pedigree with α-mannosidosis and identification of a novel missense mutation
- Are the characteristics of thyroid cancer different in young patients?
- Unsaturated fatty acids and insulin resistance in childhood obesity
- Effect of genetic subtypes and growth hormone treatment on bone mineral density in Prader-Willi syndrome
- KCNJ11 gene mutation analysis on nine Chinese patients with type 1B diabetes diagnosed before 3 years of age
- Prevalence and risk factors of metabolic syndrome in school adolescents of northeast China
- Patient reports
- A novel activating ABCC8 mutation underlying neonatal diabetes mellitus in an infant presenting with cerebral sinovenous thrombosis
- Endocrinological anomalies in a patient with 12q14 microdeletion syndrome. Completing phenotype of this exceptional short stature condition
- Acute mental status change as the presenting feature of adrenal insufficiency in a patient with autoimmune polyglandular syndrome type II and stroke
- Effect of ethosuximide on cortisol metabolism in the treatment of congenital adrenal hyperplasia
- Absence of WNT4 gene mutation in a patient with MURCS association
- Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome
- Adrenal insufficiency in association with congenital nephrotic syndrome: a case report
- Diabetic lipemia presenting as eruptive xanthomas in a child with autoimmune polyglandular syndrome type IIIa
- A case report of nephrogenic diabetes insipidus with idiopathic Fanconi syndrome in a child who presented with vitamin D resistant rickets
- Letter to the Editor
- Hyperbilirubinemia in neonates of diabetic mothers: an indirect biomarker of organ damage?
