PDF(Pubmed)
Abstract：
Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 protein expression and nuclear localization were assessed. Two Hmga2-knockin mouse models were generated. Five clinical SRS patients harbored HMGA2 variants with differing functional impacts: 2 stop-gain nonsense variants (c.49G>T, c.52C>T), c.166A>G missense variant, and 2 frameshift variants (c.144delC, c.145delA) leading to an identical, extended-length protein. Phenotypic features were highly variable. Nuclear localization was reduced/absent for all variants except c.166A>G. Homozygous knockin mice recapitulating the c.166A>G variant (Hmga2K56E) exhibited a growth-restricted phenotype. An Hmga2Ter76-knockin mouse model lacked detectable full-length Hmga2 protein, similarly to patient 3 and 5 variants. These mice were infertile, with a pygmy phenotype. We report a heterogeneous group of individuals with SRS harboring variants in HMGA2 and describe the first Hmga2 missense knockin mouse model (Hmga2K56E) to our knowledge causing a growth-restricted phenotype. In patients with clinical features of SRS but negative genetic screening, HMGA2 should be included in next-generation sequencing testing approaches.
摘要：
Silver-Russell综合征（SRS）是一种异质性疾病，其特征是子宫内和出生后生长迟缓。HMGA2变体是SRS的罕见原因，其在人类线性生长中的功能作用尚不清楚。对11p15LOM/mUPD7疑似SRS阴性的患者进行全外显子组和/或靶向基因组测序。评估突变体HMGA2蛋白表达和核定位。产生两个Hmga2-敲入小鼠模型。五名临床SRS患者携带具有不同功能影响的HMGA2变体：2个停止-增益无义变体（c.49G>T，c.52C>T)，c.166A>G错义变体，和2个移码变体(c.144delC，c.145delA)导致相同的，延长长度的蛋白质。表型特征是高度可变的。除c.166A>G外，所有变体的核定位均减少/不存在。重述c.166A>G变体（Hmga2K56E）的纯合敲入小鼠表现出生长受限的表型。Hmga2Ter76敲入小鼠模型缺乏可检测的全长Hmga2蛋白，类似于患者3和5变体。这些老鼠不育，具有侏儒表型。我们报告了一组在HMGA2中具有SRS变异体的异质个体，并描述了我们所知的第一个Hmga2错义敲入小鼠模型（Hmga2K56E），导致生长受限表型。在有SRS临床特征但遗传筛查阴性的患者中，HMGA2应包括在下一代测序测试方法中。
