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

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

  • Am J Hum Genet. 2016 Jul 7;99(1):174-87. doi: 10.1016/j.ajhg.2016.05.028.
Nikhita Ajit Bolar 1,  Christelle Golzio 2,  Martina Živná 3,  Gaëlle Hayot 2,  Christine Van Hemelrijk 4,  Dorien Schepers 1,  Geert Vandeweyer 1,  Alexander Hoischen 5,  Jeroen R Huyghe 1,  Ann Raes 4,  Erve Matthys 6,  Emiel Sys 7,  Myriam Azou 7,  Marie-Claire Gubler 8,  Marleen Praet 9,  Guy Van Camp 1,  Kelsey McFadden 2,  Igor Pediaditakis 2,  Anna Přistoupilová 3,  Kateřina Hodaňová 3,  Petr Vyleťal 3,  Hana Hartmannová 3,  Viktor Stránecký 3,  Helena Hůlková 3,  Veronika Barešová 3,  Ivana Jedličková 3,  Jana Sovová 3,  Aleš Hnízda 10,  Kendrah Kidd 11,  Anthony J Bleyer 11,  Richard S Spong 12,  Johan Vande Walle 4,  Geert Mortier 1,  Han Brunner 5,  Lut Van Laer 1,  Stanislav Kmoch 3,  Nicholas Katsanis 2,  Bart L Loeys 13
Affiliations

Affiliations

  • 1 Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
  • 2 Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA.
  • 3 Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
  • 4 Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium.
  • 5 Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
  • 6 Department of Nephrology, Sint-Jan Hospital, Brugge 8000, Belgium.
  • 7 Department of Nephrology, Sint-Lucas Hospital, Brugge 8310, Belgium.
  • 8 INSERM, U983, Paris Cedex 15, France.
  • 9 Department of Pathology, University Hospital of Ghent, Ghent 9000, Belgium.
  • 10 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic.
  • 11 Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
  • 12 Department of Medicine, Division of Renal Diseases and Hypertension, University of Minnesota, MN 55455, USA.
  • 13 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.
PMID: 27392076 DOI: 10.1016/j.ajhg.2016.05.028
Abstract

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.

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