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

Research output: Contribution to journalArticle

34 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 - 2017 Jul 1

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Autosomal Recessive Polycystic Kidney
Mutation
Proteins
Basal Bodies
Centrioles
Zebrafish
Protein Transport
Maintenance
Membranes
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Lu, H., Galeano, M. C. R., Ott, E., Kaeslin, G., Kausalya, P. J., Kramer, C., ... 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
Lu, Hao ; Galeano, Maria C.Rondón ; Ott, Elisabeth ; Kaeslin, Geraldine ; Kausalya, P. Jaya ; Kramer, Carina ; Ortiz-Brüchle, Nadina ; Hilger, Nadescha ; Metzis, Vicki ; Hiersche, Milan ; Tay, Shang Yew ; Tunningley, Robert ; Vij, Shubha ; Courtney, Andrew D. ; Whittle, Belinda ; Wühl, Elke ; Vester, Udo ; Hartleben, Björn ; Neuber, Steffen ; Frank, Valeska ; Little, Melissa H. ; Epting, Daniel ; Papathanasiou, Peter ; Perkins, Andrew C. ; Wright, Graham D. ; Hunziker, Walter ; Gee, Heon Yung ; Otto, Edgar A. ; Zerres, Klaus ; Hildebrandt, Friedhelm ; Roy, Sudipto ; Wicking, Carol ; Bergmann, Carsten. / Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. In: Nature Genetics. 2017 ; Vol. 49, No. 7. pp. 1025-1034.
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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.",
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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

Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. / Lu, Hao; Galeano, Maria C.Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P. Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D.; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H.; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C.; Wright, Graham D.; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A.; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten.

In: Nature Genetics, Vol. 49, No. 7, 01.07.2017, p. 1025-1034.

Research output: Contribution to journalArticle

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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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