Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor I receptor (IGF1R) mutation:: Implications for a gene dosage effect of the human IGF1R
Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor I receptor (IGF1R) mutation:: Implications for a gene dosage effect of the human IGF1R
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DOI：
10.1210/jc.2005-2146
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发表时间：
2006-06-01
影响因子：
5.8
通讯作者：
Kiess, W.
中科院分区：
文献类型：
--
作者：
Raile, K.;Klammt, J.;Kiess, W.
背景：通过IGF-I受体(IGF-IR)传递的信号对正常的出生前和出生后的生长至关重要。IGF-IR杂合突变Arg59Ter导致IGF-IR表达降低，代表着人类IGF1R基因的单倍性不足。目的：我们研究了人类IGF1R基因剂量效应的临床和体外方面。我们提供了这两个同父异母兄弟及其母亲Arg59Ter突变的详细临床数据。Arg59Ter和对照成纤维细胞检测胰岛素样生长因子-I和胰岛素刺激的受体磷酸化和信号转导的功能。结果：兄弟俩表现为原发性小头畸形，轻度智力低下，宫内和出生后生长缺陷。经过生长激素治疗(30微克/公斤体重)24个月，先证者生长缺陷减少+1.0SD。在所有Arg59Ter受试者中，没有临床证据表明糖耐量受损或低血糖。在体外，IGF-IR缺陷的Arg59Ter细胞表达较少的IGF-IR，而胰岛素受体(IR)蛋白没有变化。在Arg59Ter细胞中，受体自磷酸化和下游蛋白激酶B/Akt的磷酸化表现出对IGF-I的抵抗，但对胰岛素有增强的反应。IGF-IR含量降低伴随着IGF-IR/IR受体杂交体的减少，因此IR/IR同源二聚体水平的增加可能是胰岛素刺激的受体自磷酸化和Akt磷酸化增加的原因。结论：在体内和体外，Arg59Ter受试者和成纤维细胞对IGF-I的抵抗不仅与IGF-IR有关，而且与IGF-IR/IR杂交体的IGF1R基因剂量效应有关。IGF-IR蛋白和IGF-IR/IR杂合受体的丰富可能对人类的生长发育、器官功能和葡萄糖代谢产生影响。
Context: Signaling via the IGF-I receptor (IGF-IR) is crucial for normal prenatal and postnatal growth. The heterozygous IGF-IR mutation Arg59Ter resulted in reduced IGF-IR expression and represents haploinsufficiency of the human IGF1R gene.Objective: We studied clinical and in vitro aspects of a human IGF1R gene dosage effect. We provide detailed clinical data on the two half-brothers and their mother with the Arg59Ter mutation. Arg59Ter and control fibroblasts were examined for functionality of IGF-I and insulin-stimulated receptor phosphorylation and signal transduction.Results: The two brothers presented with primary microcephaly, mild mental retardation, and intrauterine as well as postnatal growth deficits. After GH therapy (30 mu g/kg(.)d) for 24 months, the growth deficit in the propositus decreased by +1.0 SD. There was no clinical evidence for impaired glucose tolerance or hypoglycemia in all Arg59Ter subjects. In vitro, IGF-IR-deficient Arg59Ter cells expressed less IGF-IR and unchanged insulin receptor (IR) protein. Receptor autophosphorylation and phosphorylation of downstream protein kinase B/Akt exhibited resistance to IGF-I but showed an augmented response to insulin in Arg59Ter cells. Decreased IGF-IR content was accompanied by a reduction of IGF-IR/IR receptor hybrids, and therefore, increased levels of IR/IR homodimers probably explain increased insulin-stimulated receptor autophosphorylation and Akt phosphorylation.Conclusions: In vivo and in vitro IGF-I resistance in Arg59Ter subjects and fibroblasts indicates a human IGF1R gene dosage effect involving not only the IGF-IR, but also IGF-IR/IR hybrids. The abundance of both the IGF-IR protein and IGF-IR/IR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.