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.
Bibliographical noteFunding Information:
B.L.L. is senior clinical investigator of the Fund for Scientific Research, Flanders (FWO, Belgium). This research was supported by funding from the Fund for Scientific Research, Flanders (FWO, Belgium) [G.0458.09; G.0221.12], the Fondation Leducq (MIBAVA 12CVD03), Starting grant (to B.L.L.) of the European Research Council (ERC- StG-2012-30972-BRAVE), and the University of Antwerp (Lanceringsproject). N.K. is a Distinguished Brumley Professor. This work was supported by grants P50DK096415 and P30DK096493 (to N.K.). S.K., A.P., K.H., and V.S. are funded by Charles University institutional programs PRVOUK-P24/LF1/3, UNCE 204011, and SVV2016/260148 and by the project LQ1604 NPU II from the Ministry of Education of the Czech Republic. This work was specifically supported by grants LH12015 from the Ministry of Education of the Czech Republic and NT13116-4/2012 from the Ministry of Education and Ministry of Health of the Czech Republic. A.P. was supported by GA UK No. 1402213. A. Hnízda was supported by the project LO1304 (program “NPU I”). A. Hoischen was supported by the Netherlands Organization for Health Research and Development (ZonMW 916-12-095). A.J.B. is supported by the US NIH grant 1R21DK106584-01.