Monk D, Wakeling E L, Proud V, Hitchins M, Abu-Amero S N, Stanier P, Preece M A, Moore G E
Action Research Laboratory for the Molecular Biology of Fetal Development, Division of Paediatrics, Obstetrics and Gynaecology, Imperial College School of Medicine, Queen Charlotte's and Chelsea Hospital, London W6 0XG, United Kingdom.
Am J Hum Genet. 2000 Jan;66(1):36-46. doi: 10.1086/302717.
Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth failure and other dysmorphic features. The syndrome is genetically heterogeneous, but maternal uniparental disomy of chromosome 7 has been demonstrated in approximately 7% of cases. This suggests that at least one gene on chromosome 7 is imprinted and involved in the pathogenesis of SRS. We have identified a de novo duplication of 7p11.2-p13 in a proband with features characteristic of SRS. FISH confirmed the presence of a tandem duplication encompassing the genes for growth factor receptor-binding protein 10 (GRB10) and insulin-like growth factor-binding proteins 1 and 3 (IGFBP1 and -3) but not that for epidermal growth factor-receptor (EGFR). Microsatellite markers showed that the duplication was of maternal origin. These findings provide the first evidence that SRS may result from overexpression of a maternally expressed imprinted gene, rather than from absent expression of a paternally expressed gene. GRB10 lies within the duplicated region and is a strong candidate, since it is a known growth suppressor. Furthermore, the mouse homologue (Grb10/Meg1) is reported to be maternally expressed and maps to the imprinted region of proximal mouse chromosome 11 that demonstrates prenatal growth failure when it is maternally disomic. We have demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting. An additional 36 SRS probands were investigated for duplication of GRB10, but none were found. However, it remains possible that GRB10 and/or other genes within 7p11.2-p13 are responsible for some cases of SRS.
Silver-Russell综合征（SRS）的特征是产前和产后生长发育迟缓以及其他畸形特征。该综合征在遗传上具有异质性，但约7%的病例中已证实存在7号染色体单亲二倍体母源。这表明7号染色体上至少有一个基因是印记基因，并参与了SRS的发病机制。我们在一名具有SRS特征的先证者中发现了7p11.2-p13的新发重复。荧光原位杂交（FISH）证实存在串联重复，该重复包含生长因子受体结合蛋白10（GRB10）以及胰岛素样生长因子结合蛋白1和3（IGFBP1和-3）的基因，但不包含表皮生长因子受体（EGFR）的基因。微卫星标记显示该重复来自母源。这些发现提供了首个证据，表明SRS可能是由母源表达的印记基因过度表达所致，而非父源表达基因的缺失表达。GRB10位于重复区域内，是一个有力的候选基因，因为它是已知的生长抑制因子。此外，据报道小鼠同源基因（Grb10/Meg1）是母源表达的，并且定位于小鼠近端11号染色体的印记区域，当该区域母源二体时会出现产前生长发育迟缓。我们已经证明GRB10基因间隔在人类淋巴细胞中异步复制，提示存在印记现象。另外对36名SRS先证者进行了GRB10重复的检测，但未发现阳性结果。然而，GRB10和/或7p11.2-p13内的其他基因仍有可能是某些SRS病例的病因。
