INSERM U781, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Am J Hum Genet. 2009 Dec;85(6):903-8. doi: 10.1016/j.ajhg.2009.11.007.
Autosomal-recessive inheritance accounts for nearly 25% of nonsyndromic mental retardation (MR), but the extreme heterogeneity of such conditions markedly hampers gene identification. Combining autozygosity mapping and RNA expression profiling in a consanguineous Tunisian family of three MR children with mild microcephaly and white-matter abnormalities identified the TRAPPC9 gene, which encodes a NF-kappaB-inducing kinase (NIK) and IkappaB kinase complex beta (IKK-beta) binding protein, as a likely candidate. Sequencing analysis revealed a nonsense variant (c.1708C>T [p.R570X]) within exon 9 of this gene that is responsible for an undetectable level of TRAPPC9 protein in patient skin fibroblasts. Moreover, TNF-alpha stimulation assays showed a defect in IkBalpha degradation, suggesting impaired NF-kappaB signaling in patient cells. This study provides evidence of an NF-kappaB signaling defect in isolated MR.
常染色体隐性遗传约占非综合征性智力障碍（MR）的 25%，但此类病症的极端异质性显著阻碍了基因的鉴定。通过对一个患有轻度小头畸形和白质异常的 MR 的 3 名近亲生育的突尼斯家族进行自体基因同质性作图和 RNA 表达谱分析，发现了 TRAPPC9 基因，该基因编码 NF-kappaB 诱导激酶（NIK）和 IkappaB 激酶复合物 β（IKK-β）结合蛋白，可能是候选基因。测序分析显示该基因第 9 外显子的一个无义变异（c.1708C>T [p.R570X]）导致患者皮肤成纤维细胞中无法检测到 TRAPPC9 蛋白。此外，TNF-α刺激试验显示 IkBalpha 降解缺陷，表明患者细胞中的 NF-kappaB 信号转导受损。本研究为孤立性 MR 中存在 NF-kappaB 信号转导缺陷提供了证据。
