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

doi:10.1038/ng.3871

Cited by 157 publications

(144 citation statements)

References 66 publications

(67 reference statements)

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“…2B). A similar phenotype has also recently reported in a Dzip1l ciliary gene mutant (Lu et al, 2017;Wang et al, 2018). Since neural tube patterning is largely dependent on Gli2 FL activator activity, this finding suggests that the Gli2 FL activator function is not significantly affected in the neural tube of Rab34 mutants.…”

Section: Discussionsupporting

confidence: 86%

Rab34 small GTPase is required for Hedgehog signaling and an early step of ciliary vesicle formation in mouse

Liu

Meng

et al. 2018

Journal of Cell Science

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The primary cilium is a microtubule-based organelle that protrudes from the cell surface and plays essential roles in embryonic development. Ciliogenesis begins with the successive fusion of preciliary vesicles to form ciliary vesicles, which then dock onto the distal end of the mother centriole. Rab proteins have been linked to cilia formation in cultured cells, but not yet in vivo. In the present study, we demonstrate that endocytic recycling protein Rab34 localizes to cilia, and that its mutation results in significant decrease of ciliogenesis in both cultured cells and mice. Rab34 is required for the successive fusion of preciliary vesicles to generate ciliary vesicles and for the migration of the mother centriole from perinuclear region to plasma membrane. We also show that Rab34 mutant mice exhibit polydactyly, and cleft-lip and-palate. These phenotypes are consistent with observations that nonciliated Rab34 mutant cells fail to respond to Hedgehog signaling and that processing of full-length Gli3 to its C-terminally truncated form is reduced in Rab34 mutant embryos. Therefore, Rab34 is required for an early step of ciliary vesicle formation and Hh signaling in vivo. This article has an associated First Person interview with the first author of the paper.

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Section: Discussionsupporting

confidence: 86%

Rab34 small GTPase is required for Hedgehog signaling and an early step of ciliary vesicle formation in mouse

Liu

Meng

et al. 2018

Journal of Cell Science

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“…For this reason, the assembly and function of the TZ is a hot topic in biomedical research. A lot of proteins participate in TZ assembly and/or function as ciliary gatekeepers at the TZ [12- 14,16,17,19,23,24,27,29,30,33,34,37,41,69,70,[73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90]. However, the relationships between these proteins and hence the mechanisms underlying ciliary gating at the TZ remain largely elusive.…”

Section: Interestingly Garcia-gonzalo Et Al Revealed That the Loss mentioning

confidence: 99%

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Wiegering

Dildrop

Vesque

et al. 2020

Preprint

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A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.

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“…These findings suggest that while expression of the cystin-GFP in collecting ducts markedly attenuated the cpk renal phenotype, sporadic cyst formation did occur in proximal tubular segments of these kidneys ( Figure 3I). 6.…”

Section: Histological Evaluation Of Cystogenesis In Rescued Cpk Micementioning

confidence: 99%

“…1 Cohort studies indicate that 75-80% of patients with typical ARPKD have mutations in the Polycystic Kidney and Hepatic Disease 1 (PKHD1) gene. [2][3][4][5] Mutations in the DZIP1L gene account for less than 0.1% of affected patients, 6 while mutations in other hepato-renal fibrocystic disease genes, eg. HNF1B, PKD1, NPHP2, NPHP3, and NPHP13, can phenocopy ARPKD.…”

Section: Introductionmentioning

confidence: 99%

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Yang¹,

O’Connor²,

Kesterson

et al. 2020

Preprint

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Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells downregulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect in CYS1.These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene. Translational Statement:The cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

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

Cited by 157 publications

References 66 publications

Rab34 small GTPase is required for Hedgehog signaling and an early step of ciliary vesicle formation in mouse

Rab34 small GTPase is required for Hedgehog signaling and an early step of ciliary vesicle formation in mouse

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

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