PUBLICATION
Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome
- Authors
- Fujita, A., Tsukaguchi, H., Koshimizu, E., Nakazato, H., Itoh, K., Kuraoka, S., Komohara, Y., Shiina, M., Nakamura, S., Kitajima, M., Tsurusaki, Y., Miyatake, S., Ogata, K., Iijima, K., Matsumoto, N., Miyake, N.
- ID
- ZDB-PUB-181115-9
- Date
- 2018
- Source
- Annals of neurology 84(6): 814-828 (Journal)
- Registered Authors
- Keywords
- Galloway-Mowat syndrome, Focal cortical dysplasia, NUP133
- MeSH Terms
-
- Animals
- Brain/growth & development
- Brain/metabolism
- Brain/pathology
- Child, Preschool
- Family Health
- Female
- Gene Expression Regulation/drug effects
- Gene Expression Regulation/genetics
- Genetic Predisposition to Disease/genetics*
- Hernia, Hiatal/diagnostic imaging
- Hernia, Hiatal/genetics*
- Hernia, Hiatal/pathology
- Humans
- Infant
- Japan
- Kidney/metabolism
- Kidney/pathology
- Kidney/ultrastructure
- Lymphocytes/metabolism
- Lymphocytes/ultrastructure
- Male
- Microcephaly/diagnostic imaging
- Microcephaly/genetics*
- Microcephaly/pathology
- Microtubule-Associated Proteins/metabolism
- Minor Histocompatibility Antigens/genetics*
- Minor Histocompatibility Antigens/ultrastructure
- Morpholinos/administration & dosage
- Mutagenesis, Site-Directed
- Mutation/genetics*
- Nephrosis/diagnostic imaging
- Nephrosis/genetics*
- Nephrosis/pathology
- Nuclear Pore Complex Proteins/genetics*
- Nuclear Pore Complex Proteins/ultrastructure
- Phosphopyruvate Hydratase/metabolism
- Young Adult
- Zebrafish
- PubMed
- 30427554 Full text @ Ann. Neurol.
Citation
Fujita, A., Tsukaguchi, H., Koshimizu, E., Nakazato, H., Itoh, K., Kuraoka, S., Komohara, Y., Shiina, M., Nakamura, S., Kitajima, M., Tsurusaki, Y., Miyatake, S., Ogata, K., Iijima, K., Matsumoto, N., Miyake, N. (2018) Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome. Annals of neurology. 84(6):814-828.
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 four subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107 kDa) mutation was identified in four GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroid-resistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133 kDa) 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 9 bp 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 three 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 wildtype NUP133 mRNA but not by mutant mRNA.
Interpretation These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS. This article is protected by copyright. All rights reserved.
Errata / Notes
This article is corrected by ZDB-PUB-220906-139 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping