Molekulare Ursachen der IGF1 Resistenz beim Menschen

3%的新生儿出生时小于胎龄儿(SGA)，其中约15%的新生儿未能赶上身高。出生SGA会带来多种不利后果，从围产期死亡率增加、心理社会或精神问题，到成年后的不利影响。躯体生长受很强的遗传因素控制，然而大多数SGA患者的病因被认为是特发性的。正在进行的项目的结果提供了证据，表明很大一部分SGA患者是影响IGF激素受体系统基因的遗传异常的携带者。新的发现包括9个新的IGF1R突变的鉴定，包括第一个纯合子氨基酸替换，第一个可能致病的IGF2点突变的检测，以及一个可能的SGA易感区域的鉴定。这些结果证实了我们的假设，这依赖于动物模型发表的信息，即很大一部分患者的SGA是由单基因干扰引起的，特别是如果出现IGF1耐药。分析在细胞内传递荷尔蒙信号的细胞质分子的畸变的研究将进入这里应用的项目的重点。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的人类突变并解开潜在的机制，可以在全身环境中对IGF系统的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、癌症以及代谢和神经退行性疾病的特定治疗具有重要意义。

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.