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

Autor:	Bolar NA; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., Golzio C; Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA., Živná M; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Hayot G; Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA., Van Hemelrijk C; Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium., Schepers D; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., Vandeweyer G; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., Hoischen A; Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands., Huyghe JR; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., Raes A; Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium., Matthys E; Department of Nephrology, Sint-Jan Hospital, Brugge 8000, Belgium., Sys E; Department of Nephrology, Sint-Lucas Hospital, Brugge 8310, Belgium., Azou M; Department of Nephrology, Sint-Lucas Hospital, Brugge 8310, Belgium., Gubler MC; INSERM, U983, Paris Cedex 15, France., Praet M; Department of Pathology, University Hospital of Ghent, Ghent 9000, Belgium., Van Camp G; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., McFadden K; Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA., Pediaditakis I; Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA., Přistoupilová A; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Hodaňová K; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Vyleťal P; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Hartmannová H; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Stránecký V; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Hůlková H; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Barešová V; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Jedličková I; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Sovová J; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Hnízda A; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic., Kidd K; Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA., Bleyer AJ; Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA., Spong RS; Department of Medicine, Division of Renal Diseases and Hypertension, University of Minnesota, MN 55455, USA., Vande Walle J; Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium., Mortier G; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., Brunner H; Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands., Van Laer L; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium., Kmoch S; Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic., Katsanis N; Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA., Loeys BL; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium; Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands. Electronic address: bart.loeys@uantwerpen.be.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2016 Jul 07; Vol. 99 (1), pp. 174-87.
DOI:	10.1016/j.ajhg.2016.05.028
Abstrakt:	Autosomal-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. (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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