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, Erve Matthys, Emiel Sys, Myriam Azou, Marie Claire Gubler, Marleen Praet, Guy Van Camp, Kelsey McFadden, Igor Pediaditakis, Anna Přistoupilová, Kateřina Hodaňová & 18 others Petr Vyleťal, 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, Bart L. Loeys

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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.

Original languageEnglish (US)
Pages (from-to)174-187
Number of pages14
JournalAmerican Journal of Human Genetics
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2016

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Kidney Diseases
Anemia
Kidney
Mutation
Atrophy
Clustered Regularly Interspaced Short Palindromic Repeats
Exome
Biopsy
Messenger RNA
Fetal Growth Retardation
Sclerosis
Zebrafish
Protein Transport
Neutropenia
Chronic Renal Insufficiency
Endoplasmic Reticulum
Kidney Transplantation
Cysts
Dialysis
Embryonic Structures

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Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia. / Bolar, Nikhita Ajit; Golzio, Christelle; Živná, Martina; Hayot, Gaëlle; Van Hemelrijk, Christine; Schepers, Dorien; Vandeweyer, Geert; Hoischen, Alexander; Huyghe, Jeroen R.; Raes, Ann; Matthys, Erve; Sys, Emiel; Azou, Myriam; Gubler, Marie Claire; Praet, Marleen; Van Camp, Guy; McFadden, Kelsey; Pediaditakis, Igor; Přistoupilová, Anna; Hodaňová, Kateřina; Vyleťal, Petr; Hartmannová, Hana; Stránecký, Viktor; Hůlková, Helena; Barešová, Veronika; Jedličková, Ivana; Sovová, Jana; Hnízda, Aleš; Kidd, Kendrah; Bleyer, Anthony J.; Spong, Richard S; Vande Walle, Johan; Mortier, Geert; Brunner, Han; Van Laer, Lut; Kmoch, Stanislav; Katsanis, Nicholas; Loeys, Bart L.

In: American Journal of Human Genetics, Vol. 99, No. 1, 07.07.2016, p. 174-187.

Research output: Contribution to journalArticle

Bolar, NA, Golzio, C, Živná, M, Hayot, G, Van Hemelrijk, C, Schepers, D, Vandeweyer, G, Hoischen, A, Huyghe, JR, Raes, A, Matthys, E, Sys, E, Azou, M, Gubler, MC, Praet, M, Van Camp, G, McFadden, K, Pediaditakis, I, Přistoupilová, A, Hodaňová, K, Vyleťal, P, Hartmannová, H, Stránecký, V, Hůlková, H, Barešová, V, Jedličková, I, Sovová, J, Hnízda, A, Kidd, K, Bleyer, AJ, Spong, RS, Vande Walle, J, Mortier, G, Brunner, H, Van Laer, L, Kmoch, S, Katsanis, N & Loeys, BL 2016, '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. https://doi.org/10.1016/j.ajhg.2016.05.028
Bolar, Nikhita Ajit ; Golzio, Christelle ; Živná, Martina ; Hayot, Gaëlle ; Van Hemelrijk, Christine ; Schepers, Dorien ; Vandeweyer, Geert ; Hoischen, Alexander ; Huyghe, Jeroen R. ; Raes, Ann ; Matthys, Erve ; Sys, Emiel ; Azou, Myriam ; Gubler, Marie Claire ; Praet, Marleen ; Van Camp, Guy ; McFadden, Kelsey ; Pediaditakis, Igor ; Přistoupilová, Anna ; Hodaňová, Kateřina ; Vyleťal, Petr ; Hartmannová, Hana ; Stránecký, Viktor ; Hůlková, Helena ; Barešová, Veronika ; Jedličková, Ivana ; Sovová, Jana ; Hnízda, Aleš ; Kidd, Kendrah ; Bleyer, Anthony J. ; Spong, Richard S ; Vande Walle, Johan ; Mortier, Geert ; Brunner, Han ; Van Laer, Lut ; Kmoch, Stanislav ; Katsanis, Nicholas ; Loeys, Bart L. / Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 1. pp. 174-187.
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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.",
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T1 - Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

AU - Bolar, Nikhita Ajit

AU - Golzio, Christelle

AU - Živná, Martina

AU - Hayot, Gaëlle

AU - Van Hemelrijk, Christine

AU - Schepers, Dorien

AU - Vandeweyer, Geert

AU - Hoischen, Alexander

AU - Huyghe, Jeroen R.

AU - Raes, Ann

AU - Matthys, Erve

AU - Sys, Emiel

AU - Azou, Myriam

AU - Gubler, Marie Claire

AU - Praet, Marleen

AU - Van Camp, Guy

AU - McFadden, Kelsey

AU - Pediaditakis, Igor

AU - Přistoupilová, Anna

AU - Hodaňová, Kateřina

AU - Vyleťal, Petr

AU - Hartmannová, Hana

AU - Stránecký, Viktor

AU - Hůlková, Helena

AU - Barešová, Veronika

AU - Jedličková, Ivana

AU - Sovová, Jana

AU - Hnízda, Aleš

AU - Kidd, Kendrah

AU - Bleyer, Anthony J.

AU - Spong, Richard S

AU - Vande Walle, Johan

AU - Mortier, Geert

AU - Brunner, Han

AU - Van Laer, Lut

AU - Kmoch, Stanislav

AU - Katsanis, Nicholas

AU - Loeys, Bart L.

PY - 2016/7/7

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N2 - 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.

AB - 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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