Study on IGF-I insensitivity : Molecular study of type 1 IGF receptor gene

背景：最近有报道称，I型胰岛素样生长因子受体(IGF-IR)基因敲除小鼠的出生体重约为野生型小鼠的45%。提示IGF-IR异常可能导致胎儿宫内发育迟缓(IUGR)。因此，我们分析了IUGR矮小患者的IGF-IR基因。对象和方法：21例IUGR矮小患者(IUGR组)，9名出生时为IUGR但直到3岁时身高正常的儿童。老年(追赶组)和18名正常成年人(对照组)。对患者和对照组的DNA进行IGF-IR基因突变分析。结果：1例患者外显子1 5‘非编码区(977-980delCTTT)存在4个碱基缺失。在另1例患者中发现新的外显子3沉默突变(204 ccc/cct)。此外，我们还发现了3个先前报道的沉默突变，分别是9例患者的第11外显子(736 ACC/ACT)、13例患者的第16外显子(1012gag/GAA)和2例患者的第21外显子(1316TAC/TAT)。在内含子中，发现两个新的单核苷酸突变：内含子13(12例患者为-53T/C)和内含子15(9例患者为+72A/G)。在20号内含子中，发现11例患者发生突变(-34G/A)。追赶组13号内含子突变发生率低于IUGR组和对照组。结论：1例患者存在外显子1 5‘非编码区4个碱基缺失。接下来，我们必须分析家族成员的IGF-IR基因，并研究该受体的功能。除了已报道的沉默突变外，我们还在外显子3、内含子13和15中发现了新的单核苷酸突变。我们将研究这些单核苷酸多态对产前生长和出生后生长的作用。

Background : A recent report showed that the birth weight of type 1 insulin-like growth factor (IGF) receptor (IGF-IR) knockout mouse is about 45 % of that of wild type mouse. This suggests that anomalies in IGF-IR may cause intra-uterine growth retardation (IUGR) in human. Therefore, we analyzed the IGF-IR gene in patients with IUGR short stature.Subjects and Methods : We employed 21 IUGR short stature patients (IUGR group), 9 children born as IUGR but became normal height until 3 yr. old (catch-up group), and 18 normal adults (control group). The DNA of the patients and control subjects was analyzed for mutations in the gene for IGF-IR.Results : Deletion of 4 bp in 5'UTR region of exon 1 (977-980 delCTTT) was found in one patient. New silent mutation in exon 3 (204 CCC/CCT) was found in another patient. In addition we found three previously reported silent mutations, exon 11 (736 ACC/ACT) in nine patients ; exon 16 (1012 GAG/GAA) in 13 patients ; and exon 21 (1316 TAC/TAT) in two patients. In introns, two new single nucleotide mutations were found in intron 13 (-53 T/C in 12 patients) and in intron 15 (+72 A/G in nine patients). In intron 20, previously reported mutation (-34 G/A) was found in 11 patients. The incidence of the mutation in intron 13 was low in the catch-up group compared with IUGR and control groups.Conclusion : Four bp deletion in 5'UTR region of exon 1 was found in one patient. Next, we must analyze the IGF-IR gene of family members, and also study the function of this receptor. In addition to previously reported silent mutations, we also found new single nucleotide mutation in exon 3, intron 13, and 15. We will study the role of these single nucleotide polymorphism on antenatal growth as well as postnatal growth.