Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Clin Invest
2018 Oct 01;12810:4313-4328. doi: 10.1172/JCI98688.
Show Gene links
Show Anatomy links
Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome.
Braun DA
,
Lovric S
,
Schapiro D
,
Schneider R
,
Marquez J
,
Asif M
,
Hussain MS
,
Daga A
,
Widmeier E
,
Rao J
,
Ashraf S
,
Tan W
,
Lusk CP
,
Kolb A
,
Jobst-Schwan T
,
Schmidt JM
,
Hoogstraten CA
,
Eddy K
,
Kitzler TM
,
Shril S
,
Moawia A
,
Schrage K
,
Khayyat AIA
,
Lawson JA
,
Gee HY
,
Warejko JK
,
Hermle T
,
Majmundar AJ
,
Hugo H
,
Budde B
,
Motameny S
,
Altmüller J
,
Noegel AA
,
Fathy HM
,
Gale DP
,
Waseem SS
,
Khan A
,
Kerecuk L
,
Hashmi S
,
Mohebbi N
,
Ettenger R
,
Serdaroğlu E
,
Alhasan KA
,
Hashem M
,
Goncalves S
,
Ariceta G
,
Ubetagoyena M
,
Antonin W
,
Baig SM
,
Alkuraya FS
,
Shen Q
,
Xu H
,
Antignac C
,
Lifton RP
,
Mane S
,
Nürnberg P
,
Khokha MK
,
Hildebrandt F
.
???displayArticle.abstract???
Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.
Ahmad,
Genetic heterogeneity in Pakistani microcephaly families revisited.
2017, Pubmed
Ahmad,
Genetic heterogeneity in Pakistani microcephaly families revisited.
2017,
Pubmed
Alazami,
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
2015,
Pubmed
Beck,
The nuclear pore complex: understanding its function through structural insight.
2017,
Pubmed
Bierzynska,
Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.
2017,
Pubmed
Blattner,
Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.
2013,
Pubmed
Boehmer,
Purification, crystallization and preliminary X-ray analysis of a Nup107-Nup133 heterodimeric nucleoporin complex.
2007,
Pubmed
Boehmer,
Depletion of a single nucleoporin, Nup107, prevents the assembly of a subset of nucleoporins into the nuclear pore complex.
2003,
Pubmed
Boyer,
INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy.
2011,
Pubmed
Braun,
Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.
2016,
Pubmed
,
Xenbase
Chaki,
Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.
2012,
Pubmed
Chatel,
Nucleoporins: leaving the nuclear pore complex for a successful mitosis.
2011,
Pubmed
D'Angelo,
A change in nuclear pore complex composition regulates cell differentiation.
2012,
Pubmed
Del Viso,
Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
2016,
Pubmed
,
Xenbase
Faul,
Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.
2007,
Pubmed
Gee,
KANK deficiency leads to podocyte dysfunction and nephrotic syndrome.
2015,
Pubmed
Gee,
ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling.
2013,
Pubmed
Gee,
FAT1 mutations cause a glomerulotubular nephropathy.
2016,
Pubmed
Gee,
Mutations in EMP2 cause childhood-onset nephrotic syndrome.
2014,
Pubmed
Giglio,
Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression.
2015,
Pubmed
Gudbjartsson,
Allegro, a new computer program for multipoint linkage analysis.
2000,
Pubmed
Halbritter,
Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.
2013,
Pubmed
Halbritter,
High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing.
2012,
Pubmed
Hall,
Rho GTPases and the control of cell behaviour.
2005,
Pubmed
Hildebrandt,
A systematic approach to mapping recessive disease genes in individuals from outbred populations.
2009,
Pubmed
Hussain,
CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.
2013,
Pubmed
Hussain,
Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.
2014,
Pubmed
Jacinto,
The nucleoporin Nup153 regulates embryonic stem cell pluripotency through gene silencing.
2015,
Pubmed
Khokha,
Techniques and probes for the study of Xenopus tropicalis development.
2002,
Pubmed
,
Xenbase
Kosinski,
Molecular architecture of the inner ring scaffold of the human nuclear pore complex.
2016,
Pubmed
Kruglyak,
Parametric and nonparametric linkage analysis: a unified multipoint approach.
1996,
Pubmed
Lovric,
Genetic testing in steroid-resistant nephrotic syndrome: when and how?
2016,
Pubmed
Lupu,
Nuclear pore composition regulates neural stem/progenitor cell differentiation in the mouse embryo.
2008,
Pubmed
MacArthur,
Guidelines for investigating causality of sequence variants in human disease.
2014,
Pubmed
Machuca,
Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology.
2009,
Pubmed
Miyake,
Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome.
2015,
Pubmed
Moawia,
Mutations of KIF14 cause primary microcephaly by impairing cytokinesis.
2017,
Pubmed
Montague,
CHOPCHOP: a CRISPR/Cas9 and TALEN web tool for genome editing.
2014,
Pubmed
Nobes,
Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility.
1995,
Pubmed
Park,
NUP107 mutations in children with steroid-resistant nephrotic syndrome.
2017,
Pubmed
Reza,
Nucleoporin gene expression in Xenopus tropicalis embryonic development.
2016,
Pubmed
,
Xenbase
Rosti,
Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.
2017,
Pubmed
Sadowski,
A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.
2015,
Pubmed
Saleem,
A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression.
2002,
Pubmed
Scott,
Podocyte-specific loss of Cdc42 leads to congenital nephropathy.
2012,
Pubmed
Seelow,
HomozygosityMapper--an interactive approach to homozygosity mapping.
2009,
Pubmed
Shang,
Molecular cloning of the rice field eel Nup93 with predominant expression in gonad and kidney.
2006,
Pubmed
Smith,
Contributions of the Transplant Registry: The 2006 Annual Report of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS).
2007,
Pubmed
Stoffel,
Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition.
2016,
Pubmed
Strauch,
Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization.
2000,
Pubmed
Szczepanski,
A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family.
2016,
Pubmed
Trautmann,
Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.
2017,
Pubmed
Van der Auwera,
From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.
2013,
Pubmed
Vivante,
Exploring the genetic basis of early-onset chronic kidney disease.
2016,
Pubmed
Vivante,
Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract.
2017,
Pubmed
von Appen,
In situ structural analysis of the human nuclear pore complex.
2015,
Pubmed
Vouillot,
Comparison of T7E1 and surveyor mismatch cleavage assays to detect mutations triggered by engineered nucleases.
2015,
Pubmed
,
Xenbase
Walther,
The conserved Nup107-160 complex is critical for nuclear pore complex assembly.
2003,
Pubmed
,
Xenbase
Wiggins,
The spectrum of podocytopathies: a unifying view of glomerular diseases.
2007,
Pubmed
Wozniak,
Nuclear transport and the mitotic apparatus: an evolving relationship.
2010,
Pubmed
Zhang,
Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.
2008,
Pubmed
Zheng,
Loss of zygotic NUP107 protein causes missing of pharyngeal skeleton and other tissue defects with impaired nuclear pore function in zebrafish embryos.
2012,
Pubmed
Zhou,
FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.
2012,
Pubmed
