Molekulare Ursachen der IGF1 Resistenz beim Menschen

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Three percent of all neonates are born small for gestational age (SGA) and about 15% of them fail to catch up height. Being born SGA entails multiple adverse consequences ranging from increased perinatal mortality, psychosocial or mental problems, up to unfavorable effects in adulthood. Somatic growth is regulated by a strong genetic component yet the etiology of most SGA patients has to be regarded as idiopathic. Results from the ongoing project have provided evidence that a significant fraction of SGA patients are carriers of genetic aberrations affecting genes of the IGF hormone – receptor system. New findings comprise the identification of 9 novel IGF1R mutations including the first homozygous amino acid substitution, the first detection for a putative pathogenic IGF2 point mutation as well as the identification of a putative SGA susceptibility region. These results corroborate our hypothesis relying on published information from animal models that SGA of a large fraction of patients, particularly if presenting with IGF1 resistance, is caused monogenic disruptions. Studies to analyze aberrations of cytoplasmic molecules that transmit the hormonal signal inside the cell will enter the focus of the project applied herein. Moreover, the more detailed clinical, genetic, and molecular biological characterization of the aforementioned mutations will provide the fundament for specific analytical future studies. The identification of human mutations causing SGA and unraveling underlying mechanisms allows a precise functional assignment of molecules of the IGF system in a whole-body setting. Due to the pleiotropic actions of the IGF system important implications for a specific treatment of growth disorders, but also cancer as well as metabolic and neurodegenerative diseases can be expected.