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      Homozygous splicing mutation in NUP13 3 causes Galloway-Mowat syndrome : Galloway-Mowat Syndrome

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          Most cited references27

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          Is Open Access

          HomozygosityMapper—an interactive approach to homozygosity mapping

          Homozygosity mapping is a common method for mapping recessive traits in consanguineous families. In most studies, applications for multipoint linkage analyses are applied to determine the genomic region linked to the disease. Unfortunately, these are neither suited for very large families nor for the inclusion of tens of thousands of SNPs. Even if less than 10 000 markers are employed, such an analysis may easily last hours if not days. Here we present a web-based approach to homozygosity mapping. Our application stores marker data in a database into which users can directly upload their own SNP genotype files. Within a few minutes, the database analyses the data, detects homozygous stretches and provides an intuitive graphical interface to the results. The homozygosity in affected individuals is visualized genome-wide with the ability to zoom into single chromosomes and user-defined chromosomal regions. The software also displays the underlying genotypes in all samples. It is integrated with our candidate gene search engine, GeneDistiller, so that users can interactively determine the most promising gene. They can at any point restrict access to their data or make it public, allowing HomozygosityMapper to be used as a data repository for homozygosity-mapping studies. HomozygosityMapper is available at http://www.homozygositymapper.org/.
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            The conserved Nup107-160 complex is critical for nuclear pore complex assembly.

            Nuclear pore complexes (NPCs) are large multiprotein assemblies that allow traffic between the cytoplasm and the nucleus. During mitosis in higher eukaryotes, the Nuclear Envelope (NE) breaks down and NPCs disassemble. How NPCs reassemble and incorporate into the NE upon mitotic exit is poorly understood. We demonstrate a function for the conserved Nup107-160 complex in this process. Partial in vivo depletion of Nup133 or Nup107 via RNAi in HeLa cells resulted in reduced levels of multiple nucleoporins and decreased NPC density in the NE. Immunodepletion of the entire Nup107-160 complex from in vitro nuclear assembly reactions produced nuclei with a continuous NE but no NPCs. This phenotype was reversible only if Nup107-160 complex was readded before closed NE formation. Depletion also prevented association of FG-repeat nucleoporins with chromatin. We propose a stepwise model in which postmitotic NPC assembly initiates on chromatin via early recruitment of the Nup107-160 complex.
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              Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

              Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.
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                Author and article information

                Journal
                Annals of Neurology
                Ann Neurol.
                Wiley
                03645134
                December 2018
                December 2018
                December 21 2018
                : 84
                : 6
                : 814-828
                Affiliations
                [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
                Article
                10.1002/ana.25370
                30427554
                3c7e1122-5e67-42b0-a9fd-2731a495f8ea
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

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