Article Text

other Versions

PDF
Hypomorphic Mutations in Meckelin (MKS3/TMEM67) cause Nephronophthisis with Liver Fibrosis (NPHP11)
  1. Edgar A Otto (eotto{at}umich.edu)
  1. Department of Pediatrics, University of Michigan, Ann Arbor, United States
    1. Kálmán Tory (torykalman{at}hotmail.com)
    1. 1st Department of Pediatrics, Semmelweis University Budapest, Hungary
      1. Massimo Attanasio (massimo.attanasio{at}utsouthwestern.edu)
      1. University of Texas, Southwestern Medical Center, Dallas, United States
        1. Weibin Zhou (weibinz{at}umich.edu)
        1. Department of Pediatrics, University of Michigan, Ann Arbor, United States
          1. Moumita Chaki (moumita{at}umich.edu)
          1. Department of Pediatrics, University of Michigan, Ann Arbor, United States
            1. Yasaswi Paruchuri (p.yasaswi{at}gmail.com)
            1. Department of Pediatrics, University of Michigan, Ann Arbor, United States
              1. Eric L Wise (ewise{at}med.wayne.edu)
              1. Department of Pediatrics, University of Michigan, Ann Arbor, United States
                1. Boris Utsch (borisutsch{at}yahoo.de)
                1. Department of Pediatrics, Inselspital, Berne, Switzerland
                  1. Matthias TF Wolf (matthias.wolf{at}childrens.com)
                  1. University of Texas, Southwestern Medical Center, Dallas, United States
                    1. Christian Becker (c.becker{at}uni-koeln.de)
                    1. Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany
                      1. Gudrun Nürnberg (gudrun.nuernberg{at}uni-koeln.de)
                      1. Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany
                        1. Peter Nürnberg (nuernberg{at}uni-koeln.de)
                        1. Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany
                          1. Ahmet Nayir (nayir{at}ttmail.com)
                          1. Department of Pediatric Nephrology, Faculty of Medicine, University of Istanbul, Istanbul, Turkey
                            1. Sophie Saunier (sophie.saunier{at}inserm.fr)
                            1. Inserm, U574, Université Paris Descartes, Faculté de médecine, Paris, France
                              1. Corinne Antignac (corinne.antignac{at}inserm.fr)
                              1. Inserm, U574, Université Paris Descartes, Faculté de médecine, Paris, France
                                1. Friedhelm Hildebrandt (fhilde{at}umich.edu)
                                1. Department of Pediatrics, University of Michigan, Ann Arbor, United States

                                  Abstract

                                  Background: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in 9 genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis.

                                  Methods: To identify a causative gene for the subset of patients with associated liver fibrosis, we performed a genome-wide linkage search in a consanguineous family with 3 affected patients using 50K SNP microarrays and homozygosity mapping.

                                  Results: We obtained a significant maximum parametric lod score of Zmax=3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a world-wide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether 4 novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in 5 of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6 are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded 7 different (4 novel) mutations in 5 patients, 4 of which presented also with congenital liver fibrosis.

                                  Conclusions: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.

                                  Statistics from Altmetric.com

                                  Request permissions

                                  If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.