13
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by mutations in the UMOD gene (ADTKD-UMOD) is considered rare and often remains unrecognised. We aimed to establish the prevalence of genetic kidney diseases, ADTKD and ADTKD-UMOD in adult chronic kidney disease (CKD) patients, and to investigate characteristic features.

          Methods

          We sent questionnaires on family history to all patients with CKD stages 3–5 in our tertiary renal centre to identify patients with inherited renal disease. Details on clinical and family history were obtained from patient interviews and clinical records. Sanger sequencing of the UMOD gene was performed from blood or saliva samples.

          Results

          2027 of 3770 sent questionnaires were returned. 459 patients reported a family history, which was consistent with inherited kidney disease in 217 patients. 182 non-responders with inherited kidney diseases were identified through a database search. Of these 399 individuals, 252 had autosomal dominant polycystic kidney disease (ADPKD), 28 had ADTKD, 25 had Alports, and 44 were unknown, resulting in 11% of CKD 3–5 patients and 19% of end-stage renal disease patients with genetic kidney diseases. Of the unknown, 40 were genotyped, of whom 31 had findings consistent with ADTKD. 30% of unknowns and 39% of unknowns with ADTKD had UMOD mutations. Altogether, 35 individuals from 18 families were found to have ten distinct UMOD mutations (three novel), making up 1% of patients with CKD 3–5, 2% of patients with end-stage renal disease, 9% of inherited kidney diseases and 56% with ADTKD. ADTKD-UMOD was the most common genetic kidney disease after ADPKD with a population prevalence of 9 per million. Less proteinuria and haematuria, but not hyperuricaemia or gout were predictive of ADTKD-UMOD. The main limitations of the study are the single-centre design and a predominantly Caucasian population.

          Conclusions

          The prevalence of genetic kidney diseases and ADTKD-UMOD is significantly higher than previously described. Clinical features poorly predicted ADTKD-UMOD, highlighting the need for genetic testing guided by family history alone.

          Electronic supplementary material

          The online version of this article (10.1186/s12882-018-1107-y) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 29

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The ExAC browser: displaying reference data information from over 60 000 exomes

          Worldwide, hundreds of thousands of humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation and understanding gene function. Here, we present a lightweight, flexible browser framework to display large population datasets of genetic variation. We demonstrate its use for exome sequence data from 60 706 individuals in the Exome Aggregation Consortium (ExAC). The ExAC browser provides gene- and transcript-centric displays of variation, a critical view for clinical applications. Additionally, we provide a variant display, which includes population frequency and functional annotation data as well as short read support for the called variant. This browser is open-source, freely available at http://exac.broadinstitute.org, and has already been used extensively by clinical laboratories worldwide.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.

            Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.

              The disease complex medullary cystic disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) is characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN is caused by mutations of the gene encoding uromodulin, the most abundant protein in urine. Here, we describe new missense mutations in three families with MCKD/FJHN and demonstrate allelism with a glomerulocystic kidney disease (GCKD) variant, showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD/FJHN as hyperuricemia and impairment of urine concentrating ability. Furthermore, we provide the first functional characterization of uromodulin mutations. The four newly identified mutants were characterized by immunofluorescence and FACS analysis on transfected cells. These experiments showed that all uromodulin mutations cause a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD/FJHN kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle's loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Consistently, patient urines show a severe reduction of excreted uromodulin. The maturation impairment is consistent with the clinical findings and suggests a pathogenetic mechanism leading to these kidney diseases.
                Bookmark

                Author and article information

                Contributors
                +44 2392 286000 , Christine.gast@doctors.org.uk
                tony.marinaki@kcl.ac.uk
                monica.arenas-hernandez@gsts.com
                campbsar@gmail.com
                e.seaby@soton.ac.uk
                r.j.pengelly@soton.ac.uk
                d.gale@ucl.ac.uk
                Thomas.connor@ouh.nhs.uk
                dave.bunyan@salisbury.nhs.uk
                khod@lf1.cuni.cz
                mzivna@lf1.cuni.cz
                skmoch@lf1.cuni.cz
                s.ennis@soton.ac.uk
                gvr1951@gmail.com
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                30 October 2018
                30 October 2018
                2018
                : 19
                Affiliations
                [1 ]ISNI 0000 0004 0392 0072, GRID grid.415470.3, Wessex Kidney Centre, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, ; Southwick Hill Road, Cosham, Portsmouth, PO6 3LY UK
                [2 ]ISNI 0000 0004 1936 9297, GRID grid.5491.9, Human Genetics and Genomic Medicine, Faculty of Medicine, , University of Southampton, ; Southampton, UK
                [3 ]GRID grid.420545.2, Purine Research Laboratory, Guys and St Thomas’ NHS Foundation Trust, ; London, UK
                [4 ]ISNI 0000 0004 0417 012X, GRID grid.426108.9, UCL Centre for Nephrology, Royal Free Hospital, ; London, UK
                [5 ]ISNI 0000 0004 0488 9484, GRID grid.415719.f, Oxford Kidney Unit, Churchill Hospital, ; Oxford, UK
                [6 ]GRID grid.433814.9, Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, ; Salisbury, UK
                [7 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, , Charles University Prague, ; Prague, Czech Republic
                Article
                1107
                10.1186/s12882-018-1107-y
                6208030
                30376835
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: Wessex Kidney Centre Charitable Research Fund
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Comments

                Comment on this article