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Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia

Nikhita Ajit Bolar, Christelle Golzio, Martina Živná, Gaëlle Hayot, CHRISTINE VAN HEMELRIJK, Dorien Schepers, Geert Vandeweyer, Alexander Hoischen, Jeroen R Huyghe, Ann Raes UGent, et al. (2016) AMERICAN JOURNAL OF HUMAN GENETICS. 99(1). p.174-187
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ENDOPLASMIC-RETICULUM STRESS, DNA-SEQUENCING DATA, SIGNAL SEQUENCE, LINKAGE ANALYSIS, GENE MUTATION, ER STRESS, TRANSLOCATION, NEPHROPATHY, GENOME, PRONEPHROS
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
99
issue
1
pages
174 - 187
Web of Science type
Article
Web of Science id
000381616600014
JCR category
GENETICS & HEREDITY
JCR impact factor
9.025 (2016)
JCR rank
8/166 (2016)
JCR quartile
1 (2016)
ISSN
0002-9297
DOI
10.1016/j.ajhg.2016.05.028
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8507636
handle
http://hdl.handle.net/1854/LU-8507636
date created
2017-02-06 08:27:32
date last changed
2017-02-06 08:27:32
@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{\textrangle}G (p.Thr185Ala) and c.200T {\textrangle} 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 \v{Z}ivn{\'a}, Martina and Hayot, Ga{\"e}lle 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 P\v{r}istoupilov{\'a}, Anna and Hoda\v{n}ov{\'a}, Kate\v{r}ina and Vylet'al, Petr and Hartmannov{\'a}, Hana and Str{\'a}neck{\'y}, Viktor and H\r{u}lkov{\'a}, Helena and Bare\v{s}ov{\'a}, Veronika and Jedli\v{c}kov{\'a}, Ivana and Sovov{\'a}, Jana and Hn{\'i}zda, Ale\v{s} 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},
  keyword      = {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},
}

Chicago
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.
APA
Bolar, Nikhita Ajit, 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.
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.
MLA
Bolar, Nikhita Ajit, Christelle Golzio, Martina Živná, 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.