Molekulare Ursachen der IGF1 Resistenz beim Menschen

3%的新生儿出生时胎龄过小（SGA），约15%的新生儿身高赶不上。出生时患有SGA会带来多种不良后果，包括围产期死亡率增加、社会心理或精神问题，以及成年后的不利影响。体细胞生长受强烈的遗传成分调节，但大多数SGA患者的病因必须被视为特发性。正在进行的项目的结果提供了证据，表明SGA患者中有很大一部分是影响IGF激素受体系统基因的遗传畸变的携带者。新发现包括鉴定9个新的IGF1R突变，包括首次纯合氨基酸替代，首次检测到推定的致病性IGF2点突变以及鉴定推定的SGA易感性区域。这些结果证实了我们的假设，依赖于动物模型的公开信息，即大部分患者的SGA，特别是出现IGF1抗性的患者，是由单基因破坏引起的。分析细胞内传递激素信号的细胞质分子畸变的研究将成为本项目应用的重点。此外，上述突变的更详细的临床、遗传和分子生物学特征将为未来的具体分析研究提供基础。识别导致SGA的人类突变并揭示潜在机制，可以在全身环境中对IGF系统分子进行精确的功能分配。由于IGF系统的多效性作用，对生长障碍的特殊治疗具有重要意义，也可用于癌症以及代谢和神经退行性疾病。

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.