University Hospital for Children and Adolescents, Centre for Paediatric Research, Leipzig, Germany.
Horm Res Paediatr. 2013;80(6):431-42. doi: 10.1159/000355410. Epub 2013 Nov 26.
The insulin-like growth factor (IGF) receptor (IGF1R) is essential for normal development and growth. IGF1R mutations cause IGF-1 resistance resulting in intrauterine and postnatal growth failure. The phenotypic spectrum related to IGF1R mutations remains to be fully understood.
Auxological and endocrinological data of a patient identified previously were assessed. The patient's fibroblasts were studied to characterize the IGF1R deletion, mRNA fate, protein expression and signalling capabilities.
The boy, who carries a heterozygous IGF1R exon 6 deletion caused by Alu element-mediated recombination and a heterozygous SHOX variant (p.Met240Ile), was born appropriate for gestational age but developed proportionate short stature postnatally. IGF-1 levels were low-normal. None of the stigmata associated with SHOX deficiency or sporadically observed in IGF1R mutation carriers were present. Nonsense-mediated mRNA decay led to a substantial decline of IGF1R dosage and IGF-1-dependent receptor autophosphorylation but not impaired downstream signalling.
We present the first detailed report of an intragenic IGF1R deletion identified in a patient who, apart from short stature, deviates from all established markers that qualify a growth-retarded child for IGF1R analysis. Although such children will usually escape routine clinical mutation screenings, they can contribute to the understanding of factors and mechanisms that cooperate with the IGF1R.
胰岛素样生长因子 (IGF) 受体 (IGF1R) 对于正常的发育和生长至关重要。IGF1R 突变导致 IGF-1 抵抗，从而导致宫内和产后生长失败。与 IGF1R 突变相关的表型谱仍有待充分理解。
评估了先前确定的患者的人体测量学和内分泌数据。研究了患者的成纤维细胞，以表征 IGF1R 缺失、mRNA 命运、蛋白表达和信号转导能力。
携带由 Alu 元件介导的重组引起的杂合 IGF1R 外显子 6 缺失和杂合 SHOX 变体（p.Met240Ile）的男孩，出生时胎龄适当，但出生后出现比例性身材矮小。IGF-1 水平处于正常低值。没有发现与 SHOX 缺乏相关的特征，也没有在 IGF1R 突变携带者中偶发观察到的特征。无义介导的 mRNA 衰变导致 IGF1R 剂量和 IGF-1 依赖性受体自身磷酸化显著下降，但下游信号转导不受影响。
我们首次详细报告了在患者中发现的 IGF1R 基因内缺失，除了身材矮小外，该患者与所有确定的标记物都不同，这些标记物使生长迟缓的儿童有资格进行 IGF1R 分析。尽管这些儿童通常会逃避常规的临床突变筛查，但它们可以帮助我们理解与 IGF1R 合作的因素和机制。
