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Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

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    SYSNO ASEP0463462
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleHeterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia
    Author(s) Bolar, N. A. (BE)
    Golzio, C. (US)
    Živná, M. (CZ)
    Hayot, G. (US)
    Van Hemelrijk, C. (BE)
    Schepers, D. (BE)
    Vandeweyer, G. (BE)
    Hoischen, A. (NL)
    Huyghe, J. R. (BE)
    Raes, A. (BE)
    Matthys, E. (BE)
    Sys, E. (BE)
    Azou, M. (BE)
    Gubler, M. C. (FR)
    Praet, M. (BE)
    Van Camp, G. (BE)
    McFadden, K. (US)
    Pediaditakis, I. (US)
    Přistoupilová, A. (CZ)
    Hodaňová, K. (CZ)
    Vyleťal, P. (CZ)
    Hartmannová, H. (CZ)
    Stránecký, V. (CZ)
    Hůlková, H. (CZ)
    Barešová, V. (CZ)
    Jedličková, I. (CZ)
    Sovová, J. (CZ)
    Hnízda, Aleš (UOCHB-X)
    Kidd, K. (US)
    Bleyer, A. J. (US)
    Spong, R. S. (US)
    Vande Walle, J. (BE)
    Mortier, G. (BE)
    Brunner, H. (NL)
    Van Laer, L. (BE)
    Kmoch, S. (CZ)
    Katsanis, N. (US)
    Loeys, B. L. (BE)
    Source TitleAmerican Journal of Human Genetics. - : Cell Press - ISSN 0002-9297
    Roč. 99, č. 1 (2016), s. 174-187
    Number of pages14 s.
    Languageeng - English
    CountryUS - United States
    KeywordsSec61 ; tubulo-interstitial kidney disease ; rare disease
    Subject RIVEB - Genetics ; Molecular Biology
    R&D ProjectsLO1304 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
    Institutional supportUOCHB-X - RVO:61388963
    UT WOS000381616600014
    EID SCOPUS84989869039
    DOI10.1016/j.ajhg.2016.05.028
    AnnotationAutosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T > G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.
    WorkplaceInstitute of Organic Chemistry and Biochemistry
    Contactasep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
    Year of Publishing2017
    Electronic addresshttp://www.sciencedirect.com/science/article/pii/S0002929716301999
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