title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
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.
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Nikhita Ajit
authors.initials: NA
authors.lastname: Bolar
authors.affiliation: Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Živná
authors.affiliation: Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Hayot
authors.affiliation: Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Hemelrijk
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Schepers
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Vandeweyer
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Jeroen R
authors.initials: JR
authors.lastname: Huyghe
authors.affiliation: Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Raes
authors.affiliation: Department of Nephrology, Sint-Jan Hospital, Brugge 8000, Belgium.
authors.forename: Erve
authors.initials: E
authors.lastname: Matthys
authors.affiliation: Department of Nephrology, Sint-Lucas Hospital, Brugge 8310, Belgium.
authors.forename: Emiel
authors.initials: E
authors.lastname: Sys
authors.affiliation: Department of Nephrology, Sint-Lucas Hospital, Brugge 8310, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Azou
authors.affiliation: INSERM, U983, Paris Cedex 15, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.affiliation: Department of Pathology, University Hospital of Ghent, Ghent 9000, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Praet
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.affiliation: Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: McFadden
authors.affiliation: Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Pediaditakis
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Přistoupilová
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hodaňová
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Vyleťal
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannová
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Hůlková
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Barešová
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Jedličková
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Sovová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Hnízda
authors.affiliation: Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Kendrah
authors.initials: K
authors.lastname: Kidd
authors.affiliation: Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bleyer
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Minnesota, MN 55455, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Spong
authors.affiliation: Department of Pediatric Nephrology, University Hospital of Ghent, Ghent 9000, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vande Walle
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Han
authors.initials: H
authors.lastname: Brunner
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp 2650, Belgium.
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.affiliation: Institute for Inherited Metabolic Disorders, Prague, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
authors.affiliation: Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry, Duke University, Durham, NC 27710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: 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.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D000740:Anemia / Q000235:genetics*; D000818:Animals; D001706:Biopsy; D002648:Child; D002908:Chronic Disease; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D005799:Genes, Dominant; D006056:Golgi Apparatus / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D009503:Neutropenia / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D000069816:SEC Translocation Channels / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D000069816:SEC Translocation Channels; C000613244:SEC61A1 protein, human