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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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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.
Keywords
ENDOPLASMIC-RETICULUM STRESS, DNA-SEQUENCING DATA, SIGNAL SEQUENCE, LINKAGE ANALYSIS, GENE MUTATION, ER STRESS, TRANSLOCATION, NEPHROPATHY, GENOME, PRONEPHROS

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MLA
Bolar, Nikhita Ajit et al. “Heterozygous Loss-of-function SEC61A1 Mutations Cause Autosomal-dominant Tubulo-interstitial and Glomerulocystic Kidney Disease with Anemia.” AMERICAN JOURNAL OF HUMAN GENETICS 99.1 (2016): 174–187. Print.
APA
Bolar, N. A., Golzio, C., Živná, M., Hayot, G., VAN HEMELRIJK, C., Schepers, D., Vandeweyer, G., et al. (2016). Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia. AMERICAN JOURNAL OF HUMAN GENETICS, 99(1), 174–187.
Chicago author-date
Bolar, Nikhita Ajit, Christelle Golzio, Martina Živná, Gaëlle Hayot, CHRISTINE VAN HEMELRIJK, Dorien Schepers, Geert Vandeweyer, et al. 2016. “Heterozygous Loss-of-function SEC61A1 Mutations Cause Autosomal-dominant Tubulo-interstitial and Glomerulocystic Kidney Disease with Anemia.” American Journal of Human Genetics 99 (1): 174–187.
Chicago author-date (all authors)
Bolar, Nikhita Ajit, Christelle Golzio, Martina Živná, Gaëlle Hayot, CHRISTINE VAN HEMELRIJK, Dorien Schepers, Geert Vandeweyer, Alexander Hoischen, Jeroen R Huyghe, Ann Raes, Erve Matthys, Emiel Sys, Myriam Azou, Marie-Claire Gubler, Marleen Praet, Guy Van Camp, Kelsey McFadden, Igor Pediaditakis, Anna Přistoupilová, Kateřina Hodaňová, Petr Vylet’al, Hana Hartmannová, Viktor Stránecký, Helena Hůlková, Veronika Barešová, Ivana Jedličková, Jana Sovová, Aleš Hnízda, Kendrah Kidd, Anthony J Bleyer, Richard S Spong, Johan Vande Walle, Geert Mortier, Han Brunner, Lut Van Laer, Stanislav Kmoch, Nicholas Katsanis, and Bart Loeys. 2016. “Heterozygous Loss-of-function SEC61A1 Mutations Cause Autosomal-dominant Tubulo-interstitial and Glomerulocystic Kidney Disease with Anemia.” American Journal of Human Genetics 99 (1): 174–187.
Vancouver
1.
Bolar NA, Golzio C, Živná M, Hayot G, VAN HEMELRIJK C, Schepers D, et al. Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia. AMERICAN JOURNAL OF HUMAN GENETICS. 2016;99(1):174–87.
IEEE
[1]
N. A. Bolar et al., “Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 99, no. 1, pp. 174–187, 2016.
@article{8507636,
  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.},
  author       = {Bolar, Nikhita Ajit and Golzio, Christelle and Živná, Martina and Hayot, Gaëlle and VAN HEMELRIJK, CHRISTINE and Schepers, Dorien and Vandeweyer, Geert and Hoischen, Alexander and Huyghe, Jeroen R and Raes, Ann and Matthys, Erve and Sys, Emiel and Azou, Myriam and Gubler, Marie-Claire and Praet, Marleen and Van Camp, Guy and McFadden, Kelsey and Pediaditakis, Igor and Přistoupilová, Anna and Hodaňová, Kateřina and Vylet'al, Petr and Hartmannová, Hana and Stránecký, Viktor and Hůlková, Helena and Barešová, Veronika and Jedličková, Ivana and Sovová, Jana and Hnízda, Aleš and Kidd, Kendrah and Bleyer, Anthony J and Spong, Richard S and Vande Walle, Johan and Mortier, Geert and Brunner, Han and Van Laer, Lut and Kmoch, Stanislav and Katsanis, Nicholas and Loeys, Bart},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {ENDOPLASMIC-RETICULUM STRESS,DNA-SEQUENCING DATA,SIGNAL SEQUENCE,LINKAGE ANALYSIS,GENE MUTATION,ER STRESS,TRANSLOCATION,NEPHROPATHY,GENOME,PRONEPHROS},
  language     = {eng},
  number       = {1},
  pages        = {174--187},
  title        = {Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2016.05.028},
  volume       = {99},
  year         = {2016},
}

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