1. Homozygous splicing mutation inNUP133 causes Galloway-Mowat syndrome
- Author
-
Mika Kitajima, Satoko Miyatake, Shohei Kuraoka, Hitoshi Nakazato, Kazumoto Iijima, Atsushi Fujita, Yoshihiro Komohara, Eriko Koshimizu, Yoshinori Tsurusaki, Noriko Miyake, Hiroyasu Tsukaguchi, Kyoko Itoh, Naomichi Matsumoto, Masaaki Shiina, Kazuhiro Ogata, and Shohei Nakamura
- Subjects
0301 basic medicine ,Microcephaly ,Mutation ,Biology ,Cortical dysplasia ,medicine.disease ,medicine.disease_cause ,Molecular biology ,Galloway Mowat syndrome ,03 medical and health sciences ,Exon ,030104 developmental biology ,Focal segmental glomerulosclerosis ,Neurology ,medicine ,Neurology (clinical) ,Nucleoporin ,Exome sequencing - Abstract
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. Ann Neurol 2018;84:814-828.
- Published
- 2018