Analyse einer genetischen Variante im Proto-Onkogen Ha-Ras – identifiziert in einem Patienten mit vorzeitigem Alterungssyndrom und Insulinresistenz

Zusammenfassung

Vererbte genetische Varianten in der durch den Insulinrezeptor initiierten zellulären Signalweiterleitung stehen schon lange im Verdacht, zur Entstehung des Typ-2-Diabetes mellitus beizutragen. In dieser Arbeit besprechen wir eine heterozygote Mutation im ersten codierenden Exon des Proto-Onkogens Ha-Ras (Ha-RasA11P), die wir bei einem Patienten mit einem familiären Voralterungssyndrom identifiziert haben. Der Patient weist atopische sklerodermitische Hautveränderungen und stoffwechselseitig eine Insulinresistenz sowie eine Störung des Fettstoffwechsels auf. In-vitro-Analysen zeigen, dass diese Mutation nicht nur die Signalweiterleitung des Insulinrezeptors, sondern auch weiterer Rezeptortyrosinkinasen, wie z. B. IGF-1, EGF, oder PDGF, unterbricht. Diese Ergebnisse demonstrieren, dass Ha-Ras eine bedeutende Rolle in der Insulinsensitivität des Menschen haben könnte.

Abstract

Inherited genetic variants of insulin receptor induced cellular signaling have long been suspected to contribute to the development of type-2- diabetes mellitus. In this report we discuss a heterozygous mutation in the first coding exon of the proto-oncogene Ha-Ras (Ha-RasA11P) that we have identified in a patient with familial premature aging syndrome. The patient has atopic sklerodermic skin alterations, insulin resistance as well as disturbances in lipid metabolism. In vitro analyzes have shown that this mutation disrupted not only the signal transduction of the insulin receptor but also other receptor tyrosine kinases, such as IGF-1, EGF, PDGF. These results demonstrate that HA-Ras might have a significant role in insulin sensitivity in humans.

Key words

Signaltransduction - MAPK cascades - Ha-Ras mutation - insulin resistance - growth regulation

Schlüsselwörter

Signaltransduktion - MAPK-Kaskaden - Ha-Ra-Mutation - Insulinresistenz - Wachstumsregulation

• Literatur

• 1 Yang SH, Sharrocks AD, Whitmarsh AJ. MAP kinase signalling cascades and transcriptional regulation. Gene 2013; 513: 1-13
• 2 Huang-Doran I, Savage DB. Congenital syndromes of severe insulin resistance. Pediatr Endocrinol Rev 2011; 8: 190-199
• 3 Taylor SI, Accili D, Haft CR et al. Mechanisms of hormone resistance: lessions from insulin resistant patients. Acta Paediatr Suppl 1994; 399: 95-104
• 4 Taylor SI, Kadowaki T, Kadowaki H et al. Mutations in insulin receptor gene in insulin-resistant patients. Diabetes Care 1990; 13: 257-279
• 5 O’Rahilly S, Moller DE. Mutant insulin receptors in syndromes of insulin resistance. Clin Endocrinol 1992; 36: 121-132
• 6 Müller-Wieland D, van der Vorm ER, Streicher R et al. An in-frame insertion in Exon 3 and a nonsence mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rhabson-Mendenhall syndrome. Diabetologia 1993; 36: 1168-1174
• 7 Kahn CR. Diabetes. Causes of insulin resistance. Nature 1995; 373: 384-385
• 8 Stears A, O’Rahilly S, Semple RK et al. Metabolic insights from extreme human insulin resistance phenotypes. Best Pract Res Clin Endocrinol Metab 2012; 26: 145-157
• 9 Soutar AK. Rare genetic causes of autosomal dominant or recessive hypercholesterolaemia. IUBMB Life 2010; 62: 125-131
• 10 Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S A 1973; 70: 2804-2808
• 11 Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 1977; 46: 897-930
• 12 Bodzioch M, Orsó E, Klucken J et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Gene 1999; 22: 347-351
• 13 Hoepffner HJ, Dreyer M, Schmidt-Preuss U et al. A new familial syndrome with impaired function of three peptide growth factors. Hum Genet 1989; 83: 209-216
• 14 Kausch C, Hamann A, Uphues I et al. Association of impaired phosphatidylinositol 3-kinase activity in GLUT1-containing vesicles with malinsertion of glucose transporters into the plasma membrane of fibroblasts from a patient with severe insulin resistance and clinical features of Werner syndrome. J Clin Endocrinol Metab 2000; 85: 905-918
• 15 Knebel B, Kotzka J, Avci H et al. Characterization of a postreceptor signaling defect that impairs cfos expression in cultured fibroblasts of a patient with insulin resistance. Biochem Biophys Res Commun 2000; 268: 577-582
• 16 Knebel B, Avci H, Bullmann C et al. Reduced phosphorylation of transcription factor Elk-1 in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance. Exp Clin Endocrinol Diabetes 2005; 113: 94-101
• 17 Chen Q, Olashaw N, Wu J. Participation of reactive oxygen species in the lysophosphatidic acid-stimulated mitogen-activated protein kinase kinase activation pathway. J Biol Chem 1995; 270: 28499-28502
• 18 Kotzka J, Knebel B, Avci H et al. Phosphorylation of sterol regulatory element-binding protein (SREBP)-1a links growth hormone action to lipid metabolism in hepatocytes. Atherosclerosis 2010; 213: 156-165
• 19 Bruder JT, Heidecker G, Rapp UR. Serum-, TPA-, and Ras-induced expression from AP-1/Ets-driven promoters require Raf-1 kinase. Genes & Dev 1992; 6: 545-556
• 20 Witzel F, Maddison L, Blüthgen N. How scaffolds shape MAPK signaling: what we know and opportunities for systems approaches. Front Physiol 2012; 3: 475
• 21 Aoki Y, Matsubara Y. The RAS/MAPK Syndromes: Novel Roles of the RAS Pathway in Human Genetic Disorders. Int J Hematol 2012;
• 22 Aoki Y, Niihori T, Narumi Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008; 29: 992-1006
• 23 Byrne JL, Paterson HF, Marshall CJ. p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus. Oncogene 1996; 13: 2055-2065
• 24 Avruch J, Khokhlatchev A, Kyriakis JM et al. Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res 2001; 56: 127-155
• 25 Gripp KW, Lin AE, Stabley DL et al. HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation. Am J Med Genet Part A 2006; 140A: 1-7
• 26 Vassy JL, Meigs JB. Is genetic testing useful to predict type 2 diabetes?. Best Pract Res Clin Endocrinol Metab 2012; 26: 189-201
• 27 Voight BF, Scott LJ, Steinthorsdottir V et al.; MAGIC investigators, GIANT Consortium Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010; 42: 579-589
• 28 Vairaktaris E, Goutzanis L, Yapijakis C et al. Diabetes enhances the expression of H-ras and suppresses the expression of EGFR leading to increased cell proliferation. Histol Histopatho 2009; 24: 531-539
• 29 Rapoport MJ, Mor A, Vardi P et al. Defective activation of p21ras in peripheral blood mononuclear cells from patients with insulin dependent diabetes mellitus. Autoimmunity 1999; 29: 147-254
• 30 Owerbach D, Gunn S, Gabbay KH. Multigenic basis for type I diabetes. Association of HRAS1 polymorphism with HLA-DR3, DQw2 / DR4, DQw8. Diabetes 1990; 39: 1504-1509
• 31 Rapoport MJ, Levi O, Weiss M et al. High insulin requirements and poor metabolic control do not modify the expression, regulation and PKC mediated activation of the p21ras pathway in PBMC from type II diabetic patients. Int J Exp Diabetes Res 2001; 2: 47-54
• 32 Gripp KW, Bifeld E, Stabley DL et al. A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development. Am J Med Genet 2012; 158A: 2106-2118