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 Frank; Melissa 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

doi:10.1038/ng.3871

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

138 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 language	English
Pages (from-to)	1025-1034
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	7
DOIs	https://doi.org/10.1038/ng.3871
Publication status	Published - 1 Jul 2017

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Lu, H., Galeano, M. C. R., Ott, E., Kaeslin, G., Kausalya, P. J., Kramer, C., Ortiz-Brüchle, N., Hilger, N., Metzis, V., Hiersche, M., Tay, S. Y., Tunningley, R., Vij, S., Courtney, A. D., Whittle, B., Wühl, E., Vester, U., Hartleben, B., Neuber, S., ... Bergmann, C. (2017). Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nature Genetics, 49(7), 1025-1034. https://doi.org/10.1038/ng.3871

@article{56c42a8945024201be724fe61dec3827,

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

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.",

author = "Hao Lu and Galeano, {Maria C.Rond{\'o}n} and Elisabeth Ott and Geraldine Kaeslin and Kausalya, {P. Jaya} and Carina Kramer and Nadina Ortiz-Br{\"u}chle and Nadescha Hilger and Vicki Metzis and Milan Hiersche and Tay, {Shang Yew} and Robert Tunningley and Shubha Vij and Courtney, {Andrew D.} and Belinda Whittle and Elke W{\"u}hl and Udo Vester and Bj{\"o}rn Hartleben and Steffen Neuber and Valeska Frank and Little, {Melissa H.} and Daniel Epting and Peter Papathanasiou and Perkins, {Andrew C.} and Wright, {Graham D.} and Walter Hunziker and Gee, {Heon Yung} and Otto, {Edgar A.} and Klaus Zerres and Friedhelm Hildebrandt and Sudipto Roy and Carol Wicking and Carsten Bergmann",

year = "2017",

month = jul,

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doi = "10.1038/ng.3871",

language = "English",

volume = "49",

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Lu, H, Galeano, MCR, Ott, E, Kaeslin, G, Kausalya, PJ, Kramer, C, Ortiz-Brüchle, N, Hilger, N, Metzis, V, Hiersche, M, Tay, SY, Tunningley, R, Vij, S, Courtney, AD, Whittle, B, Wühl, E, Vester, U, Hartleben, B, Neuber, S, Frank, V, Little, MH, Epting, D, Papathanasiou, P, Perkins, AC, Wright, GD, Hunziker, W, Gee, HY, Otto, EA, Zerres, K, Hildebrandt, F, Roy, S, Wicking, C & Bergmann, C 2017, 'Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease', Nature Genetics, vol. 49, no. 7, pp. 1025-1034. https://doi.org/10.1038/ng.3871

TY - JOUR

T1 - Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease

AU - Lu, Hao

AU - Galeano, Maria C.Rondón

AU - Ott, Elisabeth

AU - Kaeslin, Geraldine

AU - Kausalya, P. Jaya

AU - Kramer, Carina

AU - Ortiz-Brüchle, Nadina

AU - Hilger, Nadescha

AU - Metzis, Vicki

AU - Hiersche, Milan

AU - Tay, Shang Yew

AU - Tunningley, Robert

AU - Vij, Shubha

AU - Courtney, Andrew D.

AU - Whittle, Belinda

AU - Wühl, Elke

AU - Vester, Udo

AU - Hartleben, Björn

AU - Neuber, Steffen

AU - Frank, Valeska

AU - Little, Melissa H.

AU - Epting, Daniel

AU - Papathanasiou, Peter

AU - Perkins, Andrew C.

AU - Wright, Graham D.

AU - Hunziker, Walter

AU - Gee, Heon Yung

AU - Otto, Edgar A.

AU - Zerres, Klaus

AU - Hildebrandt, Friedhelm

AU - Roy, Sudipto

AU - Wicking, Carol

AU - Bergmann, Carsten

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

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U2 - 10.1038/ng.3871

DO - 10.1038/ng.3871

M3 - Article

SN - 1061-4036

VL - 49

SP - 1025

EP - 1034

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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