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

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