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Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease
LR. Claus, C. Chen, J. Stallworth, JL. Turner, GG. Slaats, AL. Hawks, H. Mabillard, SR. Senum, S. Srikanth, H. Flanagan-Steet, RJ. Louie, J. Silver, J. Lerner-Ellis, C. Morel, C. Mighton, F. Sleutels, M. van Slegtenhorst, T. van Ham, AS. Brooks,...
Language English Country United States
Document type Journal Article
Grant support
MC_EX_MR/M009203/1
Medical Research Council - United Kingdom
MR/M009203/1
Medical Research Council - United Kingdom
R01 DK059597
NIDDK NIH HHS - United States
MR/Y007808/1
Medical Research Council - United Kingdom
R35 GM142512
NIGMS NIH HHS - United States
MR/V028723/1
Medical Research Council - United Kingdom
MC_PC_14089
Medical Research Council - United Kingdom
R01 DK058816
NIDDK NIH HHS - United States
NLK
Freely Accessible Science Journals
from 1972
Open Access Digital Library
from 1972-01-01
- MeSH
- Cilia pathology MeSH
- TRPP Cation Channels genetics metabolism MeSH
- NIMA-Related Kinases genetics metabolism MeSH
- Kidney metabolism MeSH
- Humans MeSH
- Mutation MeSH
- Mice MeSH
- Infant, Newborn MeSH
- Polycystic Kidney Diseases * genetics MeSH
- Polycystic Kidney, Autosomal Dominant * pathology MeSH
- Protein Serine-Threonine Kinases genetics metabolism MeSH
- Serine genetics metabolism MeSH
- Carrier Proteins metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Infant, Newborn MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
Birmingham Women's and Children's National Health Services West Midlands Birmingham UK
Department of Biochemistry and Molecular Biology Mayo Clinic Rochester Minnesota USA
Department of Clinical Genetics Erasmus University Medical Center Rotterdam the Netherlands
Department of Clinical Genetics Odense University Hospital Odense Denmark
Department of Clinical Research University of Southern Denmark Odense Denmark
Department of Genetics and Biochemistry Clemson University Clemson South Carolina USA
Department of Genetics University Medical Center Utrecht Utrecht the Netherlands
Department of Medicine University of Toronto Toronto Ontario Canada
Department of Molecular Genetics University of Toronto Toronto Ontario Canada
Department of Nephrology and Hypertension University Medical Centre Utrecht Utrecht the Netherlands
Department of Pediatric Nephrology Wilhelmina Children's Hospital Utrecht the Netherlands
Department of Pediatrics 2nd Faculty of Medicine Charles University Prague Czech Republic
Department of Pediatrics University Hospital Ostrava Ostrava Czech Republic
Division of Nephrology and Hypertension Mayo Clinic Rochester Minnesota USA
Division of Nephrology Cliniques Universitaires Saint Luc Brussels Belgium
Division of Pediatric Nephrology and Hypertension Mayo Clinic Rochester Minnesota USA
Faculty of Medicine University of Ostrava Ostrava Czech Republic
Fundeni Clinical Institute Bucharest Romania
Hubrecht Institute for Developmental Biology and Stem Cell Research KNAW Utrecht the Netherlands
Institute Pathology and Genetic Center of Human Genetics Charleroi Belgium
Lunenfeld Tanenbaum Research Institute Toronto Ontario Canada
National Institute for Health and Care Research Biomedical Research Centre Newcastle UK
Newcastle University Translational and Clinical Research Institute Newcastle upon Tyne UK
Pathology and Laboratory Medicine Mount Sinai Hospital Toronto Ontario Canada
Recherche Expérimentale et Clinique UCLouvain Brussels Belgium
Renal Services The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle UK
Research Division Greenwood Genetic Center Greenwood South Carolina USA
References provided by Crossref.org
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- $a Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease / $c LR. Claus, C. Chen, J. Stallworth, JL. Turner, GG. Slaats, AL. Hawks, H. Mabillard, SR. Senum, S. Srikanth, H. Flanagan-Steet, RJ. Louie, J. Silver, J. Lerner-Ellis, C. Morel, C. Mighton, F. Sleutels, M. van Slegtenhorst, T. van Ham, AS. Brooks, EM. Dorresteijn, TS. Barakat, K. Dahan, N. Demoulin, EJ. Goffin, E. Olinger, Genomics England Research Consortium, M. Larsen, JM. Hertz, MR. Lilien, L. Obeidová, T. Seeman, HK. Stone, L. Kerecuk, M. Gurgu, FA. Yousef Yengej, CME. Ammerlaan, MB. Rookmaaker, C. Hanna, RC. Rogers, K. Duran, E. Peters, JA. Sayer, G. van Haaften, PC. Harris, K. Ling, JM. Mason, AM. van Eerde, R. Steet
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- $a Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
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