Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome
Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome
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DOI：
10.1002/ana.25370
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发表时间：
2018-12-01
影响因子：
11.2
通讯作者：
Miyake, Noriko
中科院分区：
文献类型：
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作者：
Fujita, Atsushi;Tsukaguchi, Hiroyasu;Miyake, Noriko
目的 Galloway-Mowat 综合征 (GAMOS) 是一种神经和肾脏疾病，以小头畸形、脑异常和早发性肾病综合征为特征。据报道，WDR73 和 KEOPS 复合体的 4 个亚基基因的双等位基因突变会导致 GAMOS。此外，尽管双等位基因 NUP107 突变最初是在类固醇抵抗性肾病综合征中发现的，但在 4 个 GAMOS 样家族中发现了相同的纯合 NUP107（核孔蛋白 107kDa）突变。 NUP107 和 NUP133（核孔蛋白 133kDa）是间期期间核膜中核孔复合体的相互作用亚基，这些蛋白质还参与有丝分裂期间的中心体定位和纺锤体组装。方法对先前报道的患有脑萎缩和类固醇抵抗性肾病综合征的 GAMOS 家族进行连锁分析和全外显子组测序。结果我们鉴定出纯合的 NUP133 突变 c.3335-11T>A，导致突变转录本中外显子 25 和 26 之间插入 9bp 的内含子序列。根据免疫沉淀测定，NUP133 突变会损害 NUP133 和 NUP107 的相互作用。重要的是，在尸检患者的大脑中发现了 IIa 型局灶性皮质发育不良，并且在 3 名检查患者的肾脏中确认了局灶节段性肾小球硬化。 nup133 敲低斑马鱼模型表现出小头畸形、神经元细胞较少、肾小球发育不全以及足细胞足突融合，这模仿了人类 GAMOS 特征。 nup133 morphant可以被人类野生型NUP133 mRNA拯救，但不能被突变体mRNA拯救。解释 这些数据表明双等位基因 NUP133 功能丧失突变导致 GAMOS。
Objective Galloway-Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early onset nephrotic syndrome. Biallelic mutations in WDR73 and the 4 subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107kDa) mutation was identified in 4 GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroid-resistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis. Methods Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid-resistant nephrotic syndrome. Results We identified a homozygous NUP133 mutation, c.3335-11T>A, which results in the insertion of 9bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the 3 examined patients. A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wild-type NUP133 mRNA but not by mutant mRNA. Interpretation These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS.