Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease

Hao Lu, Maria C.Rondón Galeano, Elisabeth Ott, Geraldine Kaeslin, P. Jaya Kausalya, Carina Kramer, Nadina Ortiz-Brüchle, Nadescha Hilger, Vicki Metzis, Milan Hiersche, Shang Yew Tay, Robert Tunningley, Shubha Vij, Andrew D. Courtney, Belinda Whittle, Elke Wühl, Udo Vester, Björn Hartleben, Steffen Neuber, Valeska FrankMelissa H. Little, Daniel Epting, Peter Papathanasiou, Andrew C. Perkins, Graham D. Wright, Walter Hunziker, Heon Yung Gee, Edgar A. Otto, Klaus Zerres, Friedhelm Hildebrandt, Sudipto Roy, Carol Wicking, Carsten Bergmann

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51 Citations (Scopus)

Abstract

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 DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

Original languageEnglish
Pages (from-to)1025-1034
Number of pages10
JournalNature Genetics
Volume49
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

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