期刊
ANNALS OF NEUROLOGY
卷 84, 期 6, 页码 814-828出版社
WILEY
DOI: 10.1002/ana.25370
关键词
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资金
- Japan Agency for Medical Research and Development (AMED) [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18kk020500]
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP17H01539, JP16H05357, JP17K10080]
- Japan Science and Technology Agency (JST) under the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems
- Takeda Science Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Science and Medical Care
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.
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