Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation

Hannah Schwarz; Bernt Popp; Rannar Airik; Nasrin Torabi; Karl X Knaup; Johanna Stoeckert; Thorsten Wiech; Kerstin Amann; André Reis; Mario Schiffer; Michael S Wiesener; Markus Schueler

doi:10.1093/hmg/ddab322

Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation

Standard

Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation. / Schwarz, Hannah; Popp, Bernt; Airik, Rannar; Torabi, Nasrin; Knaup, Karl X; Stoeckert, Johanna; Wiech, Thorsten; Amann, Kerstin; Reis, André; Schiffer, Mario; Wiesener, Michael S; Schueler, Markus.

In: HUM MOL GENET, Vol. 31, No. 9, 04.05.2022, p. 1357-1369.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Schwarz, H, Popp, B, Airik, R, Torabi, N, Knaup, KX, Stoeckert, J, Wiech, T, Amann, K, Reis, A, Schiffer, M, Wiesener, MS & Schueler, M 2022, 'Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation', HUM MOL GENET, vol. 31, no. 9, pp. 1357-1369. https://doi.org/10.1093/hmg/ddab322

APA

Schwarz, H., Popp, B., Airik, R., Torabi, N., Knaup, K. X., Stoeckert, J., Wiech, T., Amann, K., Reis, A., Schiffer, M., Wiesener, M. S., & Schueler, M. (2022). Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation. HUM MOL GENET, 31(9), 1357-1369. https://doi.org/10.1093/hmg/ddab322

Vancouver

Schwarz H, Popp B, Airik R, Torabi N, Knaup KX, Stoeckert J et al. Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation. HUM MOL GENET. 2022 May 4;31(9):1357-1369. https://doi.org/10.1093/hmg/ddab322

Bibtex

@article{a7259dc69f9d443a8dc1c4954f17b753,

title = "Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation",

abstract = "Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represents one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remain unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late-onset chronic kidney disease by whole-exome sequencing. We employed patient-derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient-derived cells showed an impaired integrity of the ciliary inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear yes-associated protein (YAP) imbalance and disrupted ciliary localization of YAP. In addition, an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) β-catenin and phosphorylated glycogen synthase kinase 3β were observed. Upon ciliation, ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway, and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.",

keywords = "Cilia/pathology, Ciliopathies/metabolism, Female, Humans, Kidney Diseases, Cystic/metabolism, Male, Mutation, Nuclear Proteins, Polycystic Kidney Diseases/genetics, Renal Insufficiency, Chronic",

author = "Hannah Schwarz and Bernt Popp and Rannar Airik and Nasrin Torabi and Knaup, {Karl X} and Johanna Stoeckert and Thorsten Wiech and Kerstin Amann and Andr{\'e} Reis and Mario Schiffer and Wiesener, {Michael S} and Markus Schueler",

year = "2022",

month = may,

day = "4",

doi = "10.1093/hmg/ddab322",

language = "English",

volume = "31",

pages = "1357--1369",

journal = "HUM MOL GENET",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

RIS

TY - JOUR

T1 - Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation

AU - Schwarz, Hannah

AU - Popp, Bernt

AU - Airik, Rannar

AU - Torabi, Nasrin

AU - Knaup, Karl X

AU - Stoeckert, Johanna

AU - Wiech, Thorsten

AU - Amann, Kerstin

AU - Reis, André

AU - Schiffer, Mario

AU - Wiesener, Michael S

AU - Schueler, Markus

PY - 2022/5/4

Y1 - 2022/5/4

N2 - Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represents one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remain unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late-onset chronic kidney disease by whole-exome sequencing. We employed patient-derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient-derived cells showed an impaired integrity of the ciliary inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear yes-associated protein (YAP) imbalance and disrupted ciliary localization of YAP. In addition, an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) β-catenin and phosphorylated glycogen synthase kinase 3β were observed. Upon ciliation, ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway, and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.

AB - Nephronophthisis-related ciliopathies (NPHP-RC) comprises a group of inherited kidney diseases, caused by mutations in genes encoding proteins localizing to primary cilia. NPHP-RC represents one of the most frequent monogenic causes of renal failure within the first three decades of life, but its molecular disease mechanisms remain unclear. Here, we identified biallelic ANKS6 mutations in two affected siblings with late-onset chronic kidney disease by whole-exome sequencing. We employed patient-derived fibroblasts generating an in vitro model to study the precise biological impact of distinct human ANKS6 mutations, completed by immunohistochemistry studies on renal biopsy samples. Functional studies using patient-derived cells showed an impaired integrity of the ciliary inversin compartment with reduced cilia length. Further analyses demonstrated that ANKS6 deficiency leads to a dysregulation of Hippo-signaling through nuclear yes-associated protein (YAP) imbalance and disrupted ciliary localization of YAP. In addition, an altered transcriptional activity of canonical Wnt target genes and altered expression of non-phosphorylated (active) β-catenin and phosphorylated glycogen synthase kinase 3β were observed. Upon ciliation, ANKS6 deficiency revealed a deranged subcellular localization and expression of components of the endocytic recycling compartment. Our results demonstrate that ANKS6 plays a key role in regulating the Hippo pathway, and ANKS6 deficiency is linked to dysregulation of signaling pathways. Our study provides molecular clues in understanding pathophysiological mechanisms of NPHP-RC and may offer new therapeutic targets.

KW - Cilia/pathology

KW - Ciliopathies/metabolism

KW - Female

KW - Humans

KW - Kidney Diseases, Cystic/metabolism

KW - Male

KW - Mutation

KW - Nuclear Proteins

KW - Polycystic Kidney Diseases/genetics

KW - Renal Insufficiency, Chronic

U2 - 10.1093/hmg/ddab322

DO - 10.1093/hmg/ddab322

M3 - SCORING: Journal article

C2 - 34740236

VL - 31

SP - 1357

EP - 1369

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 9

ER -