Analyses of a deactivation genetic variation in Ha-Ras proto oncogene identified in a patient wit premature aging and insulin resistance

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 has a significant role in insulin sensitivity in humans. We used microarrays to determine differences in gene expression due to a deactivating Ha-Ras mutation reducing c-fos expression in a patient with lipodystrophy and a Werner-like syndrome. Cultued fibroblasts of non diabetic controls and a patient with deactivating Ha-Ras mutation were analyzed at identical passage number and growth conditions without further additional treatment.