Hao Lu1,*, Maria C. Rondón Galeano2,*, Elisabeth Ott3,*, Geraldine Kaeslin2, P. Jaya Kausalya1, Carina Kramer3, Nadina Ortiz-Brüchle2, Nadescha Hilger4, Vicki Metzis2,$, Milan Hiersche5, Shang Yew Tay1, Robert Tunningley6, Shubha Vij1,&, Andrew D. Courtney2, Belinda Whittle6, Elke Wühl7, Udo Vester8, Björn Hartleben9, Steffen Neuber5, Valeska Frank5, Melissa H. Little2,^, Daniel Epting3, Peter Papathanasiou6,@, Andrew C. Perkins2,10, Graham D.Wright11, Walter Hunziker1,12,13, Heon Yung Gee14,15, Edgar A. Otto16, Klaus Zerres4, Friedhelm Hildebrandt14, Sudipto Roy1,17,18, Carol Wicking2,# and Carsten Bergmann3,4,5,#
1 Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore
2 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
3 Renal Division, Department of Medicine, University of Freiburg Medical Center, 79106 Freiburg, Germany
4 Institute of Human Genetics, RWTH Aachen University, 52074 Aachen, Germany
5 Center for Human Genetics, Bioscientia, 55218 Ingelheim, Germany
6 John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia
7 Division of Pediatric Nephrology, University Children’s Hospital Center for Child and Adolescent Medicine, Heidelberg University Hospital Heidelberg, 69120 Heidelberg, Germany
8 Department of Pediatric Nephrology, University Children’s Hospital Essen, 45147 Essen, Germany
9 Institute of Pathology, MHH University Medical School Hannover, 30625 Hannover, Germany
10 Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, QLD, Australia
11 Institute of Medical Biology, A*STAR, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648
12 Department of Physiology, Yong Loo Lin School of Medicine, National University of 33 Singapore, Singapore 117599
13 Singapore Eye Research Institute, Singapore 169856
14 Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
15 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
16 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA
17 Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119288
18 Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
$ The Francis Crick Institute, London NW1 1AT, UK
& Temasek Life Sciences Laboratory Limited, National University of Singapore, Singapore 117604
^ Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
@ Department of Materials, Imperial College London, London SW7 2AZ, UK
*,# These authors contributed equally
Correspondence should be addressed to
Sudipto Roy (firstname.lastname@example.org),
Carol Wicking (email@example.com),
or Carsten Bergmann (firstname.lastname@example.orgemail@example.com).
Published online in Nature Genetics on 22 May 2017.
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in the DAZ interacting protein 1-like (DZIP1L) gene in patients with ARPKD, findings we have further validated by loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and at the distal end of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. Consistent with a defect in the diffusion barrier, we found that the ciliary membrane translocation of the PKD proteins, polycystin-1 and -2, is compromised in DZIP1L mutant cells. Together, these data provide the first conclusive evidence that ARPKD is not a homogeneous disorder, and establishes DZIP1L as a second gene involved in its pathogenesis.
Mapping of a new autosomal polycystic kidney disease (ARPKD) locus on 3q22.1-q23 and identification of DZIP1L mutations. Genome-wide SNP analysis performed in two unrelated consanguineous multiplex pedigrees (shown at the top) with a total of five children affected by ARPKD, resulted in identification of a single overlapping 7.5 Mb region of homozygosity on chromosome 3q22.1-q23. By various sequencing approaches, we identified different homozygous DZIP1L mutations in these and other consanguineous families with ARPKD. In parallel, we identified an ENU-induced ARPKD mouse model bearing the homozygous Dzip1l nonsense mutation c.1123C>T (p.Gln375*) (in blue).
For more information on Sudipto ROY's lab, please click here.