PUBLICATION
Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome
- Authors
- Miyake, N., Tsukaguchi, H., Koshimizu, E., Shono, A., Matsunaga, S., Shiina, M., Mimura, Y., Imamura, S., Hirose, T., Okudela, K., Nozu, K., Akioka, Y., Hattori, M., Yoshikawa, N., Kitamura, A., Cheong, H.I., Kagami, S., Yamashita, M., Fujita, A., Miyatake, S., Tsurusaki, Y., Nakashima, M., Saitsu, H., Ohashi, K., Imamoto, N., Ryo, A., Ogata, K., Iijima, K., Matsumoto, N.
- ID
- ZDB-PUB-150929-14
- Date
- 2015
- Source
- American journal of human genetics 97(4): 555-66 (Journal)
- Registered Authors
- Yamashita, Michiaki
- Keywords
- none
- MeSH Terms
-
- Age of Onset*
- Alleles
- Animals
- Cells, Cultured
- Child
- Child, Preschool
- Cytoplasm/metabolism
- Female
- Haplotypes
- Humans
- Immunoblotting
- Immunoprecipitation
- Infant
- Kidney/metabolism
- Kidney/pathology
- Male
- Microscopy, Fluorescence
- Mutation/genetics*
- Nephrotic Syndrome/congenital*
- Nephrotic Syndrome/etiology
- Nephrotic Syndrome/pathology
- Nuclear Pore
- Nuclear Pore Complex Proteins/antagonists & inhibitors
- Nuclear Pore Complex Proteins/genetics*
- Oligoribonucleotides, Antisense/pharmacology
- Pedigree
- Podocytes/metabolism
- Podocytes/pathology
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Zebrafish/genetics*
- Zebrafish/growth & development
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics*
- PubMed
- 26411495 Full text @ Am. J. Hum. Genet.
Citation
Miyake, N., Tsukaguchi, H., Koshimizu, E., Shono, A., Matsunaga, S., Shiina, M., Mimura, Y., Imamura, S., Hirose, T., Okudela, K., Nozu, K., Akioka, Y., Hattori, M., Yoshikawa, N., Kitamura, A., Cheong, H.I., Kagami, S., Yamashita, M., Fujita, A., Miyatake, S., Tsurusaki, Y., Nakashima, M., Saitsu, H., Ohashi, K., Imamoto, N., Ryo, A., Ogata, K., Iijima, K., Matsumoto, N. (2015) Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome. American journal of human genetics. 97(4):555-66.
Abstract
The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRNS). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high frequency. NUP107 is ubiquitously expressed, including in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hamper NUP107 binding to NUP133 (nucleoporin 133 kDa) and NUP107 incorporation into NPCs in vitro. Zebrafish with nup107 knockdown generated by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, thereby mimicking the pathological changes seen in the kidneys of the SRNS individuals with NUP107 mutations. Considering the unique properties of the podocyte (highly differentiated foot-process architecture and slit membrane and the inability to regenerate), we propose a "podocyte-injury model" as the pathomechanism for SRNS due to biallelic NUP107 mutations.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping