索托斯综合征患者中NSD1基因的突变与胰岛素样生长因子（IGF）系统的内分泌和旁分泌改变相关。

Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system.

作者信息

De Boer L, Van Duyvenvoorde H A, Willemstein-Van Hove E C, Hoogerbrugge C M, Van Doorn J, Maassen J A, Karperien M, Wit J M

机构信息

Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

出版信息

Eur J Endocrinol. 2004 Sep;151(3):333-41. doi: 10.1530/eje.0.1510333.

DOI:10.1530/eje.0.1510333

PMID:15362962

Abstract

OBJECTIVE

To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level.

DESIGN

Twenty-nine patients suspected of Sotos syndrome were divided into two groups: patients with heterozygous deletions or mutations in the NSD1 gene (NSD1(+/-)) (n=11) and subjects without (NSD1(+/+)) (n=18). Plasma samples (n=29) and skin fibroblasts (n=23) were obtained. The results of both groups were compared and related to reference values.

METHODS

IGF-I, IGF-II, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6 levels were determined by RIAs. The mitogenic response of fibroblasts to IGFs was investigated by [methyl-(3)H]thymidine incorporation. IGFBP-3 levels in the culture media were measured by RIA. IGFBP-3 mRNA expression was determined by real time RT-PCR.

RESULTS

NSD1(+/-) patients showed significantly altered levels of IGF-I (mean-1.2 SDS), IGF-II (-1.2), IGFBP-3 (-1.7), IGFBP-4 (-0.4), IGFBP-2 (+0.8) and IGFBP-6 (+1.5). The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3). Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02). Compared with control fibroblasts, only the mitogenic response was diminished (basal, P=0.07; IGF-I, P=0.04; IGF-II, P=0.04). A trend of higher IGFBP-3 secretion after IGF-I stimulation (P=0.09) and 3.5-5 times higher mRNA expression of IGFBP-3 in basal conditions was found in NSD1(+/-) fibroblasts in comparison to controls.

CONCLUSIONS

NSD1(+/-) patients show endocrine and paracrine changes in the IGF system. These changes may contribute to the abnormal growth pattern.

摘要

目的

研究核受体含Su-var、3-9、zeste增强子、三体胸苷（SET）结构域蛋白1（NSD1）基因改变对Sotos综合征患者血浆胰岛素样生长因子（IGFs）和胰岛素样生长因子结合蛋白（IGFBPs）的影响，以及对组织水平上IGF/IGFBP系统活性的影响。

设计

将29例疑似Sotos综合征患者分为两组：NSD1基因杂合缺失或突变患者（NSD1(+/-)）（n = 11）和无该基因改变的受试者（NSD1(+/+)）（n = 18）。采集血浆样本（n = 29）和皮肤成纤维细胞（n = 23）。比较两组结果并与参考值相关联。

方法

采用放射免疫分析法（RIAs）测定IGF-I、IGF-II、IGFBP-2、IGFBP-3、IGFBP-4和IGFBP-6水平。通过[甲基-(3)H]胸腺嘧啶核苷掺入法研究成纤维细胞对IGFs的促有丝分裂反应。采用放射免疫分析法测定培养基中IGFBP-3水平。通过实时逆转录聚合酶链反应（RT-PCR）测定IGFBP-3 mRNA表达。

结果

NSD（+/-）患者的IGF-I（平均-1.2 SDS）、IGF-II（-1.2）、IGFBP-3（-1.7）、IGFBP-4（-0.4）、IGFBP-2（+0.8）和IGFBP-6（+1.5）水平显著改变。NSD1(+/+)患者除平均IGFBP-3水平（-1.3）外，与参考值无差异。与NSD1(+/+)成纤维细胞相比，NSD1(+/-)成纤维细胞的基础增殖和对IGFs的促有丝分裂反应减弱（基础，P = 0.02；IGF-I，P < 0.001；IGF-II，P = 0.02）。与对照成纤维细胞相比，仅促有丝分裂反应减弱（基础，P = 0.07；IGF-I，P = 0.04；IGF-II，P = 0.04）。与对照组相比，NSD1(+/-)成纤维细胞在IGF-I刺激后IGFBP-3分泌有升高趋势（P = 0.09），基础条件下IGFBP-3 mRNA表达高3.5 - 5倍。