Atsushi Fujita1, Hiroyasu Tsukaguchi2, Eriko Koshimizu1, Hitoshi Nakazato3, Kyoko Itoh4, Shohei Kuraoka3, Yoshihiro Komohara5, Masaaki Shiina6, Shohei Nakamura1, Mika Kitajima7, Yoshinori Tsurusaki8, Satoko Miyatake1, Kazuhiro Ogata6, Kazumoto Iijima9, Naomichi Matsumoto1, Noriko Miyake1. 1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama. 2. Second Department of Internal Medicine, Kansai Medical University, Osaka. 3. Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto. 4. Department of Pathology and Applied Neurobiology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto. 5. Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto. 6. Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama. 7. Department of Diagnostic Radiology, Faculty of Life Sciences, Kumamoto University, Kumamoto. 8. Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama. 9. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
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.
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.
Authors: Ginevra Zanni; P De Magistris; M Nardella; E Bellacchio; S Barresi; A Sferra; A Ciolfi; M Motta; H Lue; D Moreno-Andres; M Tartaglia; E Bertini; Wolfram Antonin Journal: Cerebellum Date: 2019-06 Impact factor: 3.847
Authors: Pamela Magini; Daphne J Smits; Laura Vandervore; Rachel Schot; Marta Columbaro; Esmee Kasteleijn; Mees van der Ent; Flavia Palombo; Maarten H Lequin; Marjolein Dremmen; Marie Claire Y de Wit; Mariasavina Severino; Maria Teresa Divizia; Pasquale Striano; Natalia Ordonez-Herrera; Amal Alhashem; Ahmed Al Fares; Malak Al Ghamdi; Arndt Rolfs; Peter Bauer; Jeroen Demmers; Frans W Verheijen; Martina Wilke; Marjon van Slegtenhorst; Peter J van der Spek; Marco Seri; Anna C Jansen; Rolf W Stottmann; Robert B Hufnagel; Robert J Hopkin; Deema Aljeaid; Wojciech Wiszniewski; Pawel Gawlinski; Milena Laure-Kamionowska; Fowzan S Alkuraya; Hanah Akleh; Valentina Stanley; Damir Musaev; Joseph G Gleeson; Maha S Zaki; Nicola Brunetti-Pierri; Gerarda Cappuccio; Bella Davidov; Lina Basel-Salmon; Lily Bazak; Noa Ruhrman Shahar; Aida Bertoli-Avella; Ghayda M Mirzaa; William B Dobyns; Tommaso Pippucci; Maarten Fornerod; Grazia M S Mancini Journal: Am J Hum Genet Date: 2019-09-05 Impact factor: 11.025
Authors: Ibrahim Sandokji; Jonathan Marquez; Weizhen Ji; Cynthia A Zerillo; Monica Konstantino; Saquib A Lakhani; Mustafa K Khokha; Jillian K Warejko Journal: BMC Nephrol Date: 2019-07-17 Impact factor: 2.388