Mutation at cleavage site of insulin-like growth factor receptor in a short- stature child born with intrauterine growth retardation
Mutation at cleavage site of insulin-like growth factor receptor in a short- stature child born with intrauterine growth retardation
复制标题
DOI：
10.1210/jc.2004-1947
复制
发表时间：
2005-08-01
影响因子：
5.8
通讯作者：
Takahashi, S
中科院分区：
文献类型：
--
作者：
Kawashima, Y;Kanzaki, S;Takahashi, S
内容：IGF-I和IGF-IR基因敲除小鼠模型已经清楚地证明了IGF-I和IGF-IR对胚胎生长以及出生后生长的关键重要性。目的：我们假设IGF-IR基因突变可能使出生的宫内生长迟缓（IUGR）儿童易于身材矮小。患者：对24例不明原因IUGR（出生体重<-1.5SD）和身材矮小（<-2.0SD）患儿进行IGF-IR基因突变筛查。免疫印迹分析检测成纤维细胞中未加工的IGF-IR前体受体。通过IGF-I结合、IGF-I刺激的DNA合成和β亚基自身磷酸化来评价突变的IGF-IR在成纤维细胞中的功能。1）在一例6岁日本女孩（病例1）及其母亲（病例2）中发现了一个杂合突变（R709 Q），将切割位点从Arg-Lys-Arg-Arg变为Arg-Lys-Gln-Arg;（2）病例2的成纤维细胞含有更多的IGF-IR前体受体蛋白（正常值的189 +/- 26%）和较不成熟的β亚基蛋白（63 +/- 12%）; 3）与正常对照相比，病例2的[I-125] IGF-I与成纤维细胞的结合减少（0.61 +/- 0.16 x 10（6）vs. 1.14 +/- 0.12 x 10（6）位点/细胞; P < 0.05）; 4）与对照组相比，病例2的成纤维细胞中IGF-I刺激的[H-3]胸苷掺入和IGF-IR β亚基自磷酸化均较低结论：该突变导致IGF-IR前体受体向成熟IGF-IR的转化失败，从而导致矮小和IUGR。
Context: Mouse knockout models have clearly demonstrated the critical importance of IGF-I and IGF receptor type 1 (IGF-IR) for embryonic growth as well as postnatal growth.Objective: We hypothesized that mutations of IGF-IR gene might predispose to short stature in children born with intrauterine growth retardation (IUGR).Patients: Twenty-four children with unexplained IUGR (birth weight < -1.5 SD) and short stature (< -2.0 SD) were screened for abnormalities of the IGF-IR gene.Methods: Direct DNA sequencing was used to identify IGF-IR gene mutations. Unprocessed IGF-IR proreceptor in fibroblasts was detected by immunoblot analysis. Functions of mutated IGF-IR in fibroblasts were evaluated by IGF-I binding, and IGF-I-stimulated DNA synthesis and beta-subunit autophosphorylation.Results: We found the following results: 1) a heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-yr-old Japanese girl (case 1) and her mother who also had IUGR with short stature (case 2); 2) fibroblasts from case 2 contained more IGF-IR proreceptor protein (189 +/- 26% of normal) and less mature beta-subunit protein (63 +/- 12%); 3) [I-125] IGF-I binding to fibroblasts from case 2 was reduced, compared with normal control (0.61 +/- 0.16 x 10(6) vs. 1.14 +/- 0.12 x 10(6) sites per cell; P < 0.05); and 4) both IGF-I-stimulated [H-3] thymidine incorporation and IGF-IR beta-subunit autophosphorylation were low in fibroblasts from case 2, compared with those of control (P < 0.05).Conclusions: These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.