AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France.
J Med Genet. 2013 Dec;50(12):823-30. doi: 10.1136/jmedgenet-2013-101691. Epub 2013 Sep 24.
Russell Silver syndrome (RSS) leads to prenatal and postnatal growth retardation. About 55% of RSS patients present a loss-of-methylation of the paternal ICR1 domain on chromosome 11p15. CDKN1C is a cell proliferation inhibitor encoded by an imprinted gene in the 11p15 ICR2 domain. CDKN1C mutations lead to Beckwith Wiedemann syndrome (BWS, overgrowth syndrome) and in IMAGe syndrome which associates growth retardation and adrenal insufficiency. We searched for CDKN1C mutations in a cohort of clinically diagnosed RSS patients with no molecular anomaly.
The coding sequence and intron-exon boundaries of CDKN1C were analysed in 97 RSS patients. The impact of CDKN1C variants on the cell cycle in vitro were determined by flow cytometry. Stability of CDKN1C was studied by western immunoblotting after inhibition of translation with cycloheximide.
We identified the novel c.836G>[G;T] (p.Arg279Leu) mutation in a familial case of intrauterine growth retardation (IUGR) with RSS phenotype and no evidence of IMAGe. All the RSS patients inherited this mutation from their mothers (consistent with monoallelic expression from the maternal allele of the gene). A mutation of this amino acid (p.Arg279Pro) has been reported in cases of IMAGe. Functional analysis showed that Arg279Leu (RSS) did not affect the cell cycle, whereas the Arg279Pro mutation (IMAGe) led to a gain of function. Arg279Leu (RSS) led to an increased stability which could explain an increased activity of CDKN1C.
CDKN1C mutations cause dominant maternally transmitted RSS, completing the molecular mirror with BWS. CDKN1C should be investigated in cases with family history of RSS.
Russell Silver 综合征（RSS）导致产前和产后生长迟缓。大约 55%的 RSS 患者在 11p15 染色体上表现出父系 ICR1 结构域的去甲基化。CDKN1C 是一个位于 11p15 ICR2 结构域内印记基因编码的细胞增殖抑制剂。CDKN1C 突变导致 Beckwith-Wiedemann 综合征（BWS，过度生长综合征）和 IMAGe 综合征，这两种综合征均与生长迟缓伴肾上腺功能不全相关。我们在一组无分子异常的临床诊断为 RSS 的患者中搜索 CDKN1C 突变。
分析了 97 例 RSS 患者的 CDKN1C 编码序列和内含子-外显子边界。通过流式细胞术确定 CDKN1C 变异对细胞周期的影响。用环已酰亚胺抑制翻译后，通过 Western 免疫印迹研究 CDKN1C 的稳定性。
我们在一例宫内生长迟缓（IUGR）伴 RSS 表型且无 IMAGe 证据的家族性病例中发现了新的 c.836G>[G；T]（p.Arg279Leu）突变。所有 RSS 患者均从母亲那里遗传了该突变（与该基因的母等位基因的单等位基因表达一致）。该氨基酸的突变（p.Arg279Pro）已在 IMAGe 病例中报道。功能分析表明 Arg279Leu（RSS）不影响细胞周期，而 Arg279Pro 突变（IMAGe）导致功能获得。Arg279Leu（RSS）导致稳定性增加，这可以解释 CDKN1C 活性增加。
CDKN1C 突变导致显性母系 RSS，与 BWS 形成分子镜像。应在 RSS 家族史病例中研究 CDKN1C。
