Kidney Week

Abstract: PO1246

Heterozygous Variants in NEK8 Kinase Domain Cause an Autosomal-Dominant Ciliopathy

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Claus, Laura R., University Medical Center Utrecht, Department of Genetics, Utrecht, Utrecht, Netherlands

Laura R. Claus, MD, PhD

• Stallworth, Jennifer, Greenwood Genetic Center Inc, Greenwood, South Carolina, United States

Jennifer Stallworth,

• van Jaarsveld, Richard H., University Medical Center Utrecht, Department of Genetics, Utrecht, Utrecht, Netherlands

Richard H. van Jaarsveld,

• Louie, Raymond, Greenwood Genetic Center Inc, Greenwood, South Carolina, United States

Raymond Louie,

• Silver, Josh, The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada

Josh Silver,

• Lerner-Ellis, Jordan, Mount Sinai Hospital Pathology and Laboratory Medicine, Toronto, Ontario, Canada

Jordan Lerner-Ellis,

• Morel, Chantal F., The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada

Chantal F. Morel,

• Mighton, Chloe, Mount Sinai Hospital Pathology and Laboratory Medicine, Toronto, Ontario, Canada

Chloe Mighton,

• Ziegler, Alban, Department of Genetics, University Hospital of Angers, Angers, France

Alban Ziegler,

• Barakat, Tahsin Stefan, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands

Tahsin Stefan Barakat,

• Dahan, Karin, Institut de Pathologie et de Genetique asbl, Gosselies, Belgium

Karin Dahan,

• Demoulin, Nathalie, Department of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Louvain, Belgium

Nathalie Demoulin,

• Goffin, Eric, Department of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Louvain, Belgium

Eric Goffin,

• Larsen, Martin Jakob, Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

Martin Jakob Larsen,

• Hertz, Jens Michael, Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

Jens Michael Hertz,

• Lilien, Marc, Department of Pediatric Nephrology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands

Marc Lilien,

• Olinger, Eric Gregory, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

Eric Gregory Olinger,

• Sayer, John Andrew, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

John Andrew Sayer,

• Obeidova, Lena, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia

Lena Obeidova,

• Seeman, Tomas, Dr von Haunersches Kinderspital Kinderklinik und Kinderpoliklinik der Ludwig Maximilian Universitat Munchen, Munchen, Bayern, Germany

Tomas Seeman,

• Rogers, Richard Curtis, Greenwood Genetic Center Inc, Greenwood, South Carolina, United States

Richard Curtis Rogers,

• Duran, Karen J., University Medical Center Utrecht, Department of Genetics, Utrecht, Utrecht, Netherlands

Karen J. Duran,

• van Haaften, Gijs W., University Medical Center Utrecht, Department of Genetics, Utrecht, Utrecht, Netherlands

Gijs W. van Haaften,

• Steet, Richard, Greenwood Genetic Center Inc, Greenwood, South Carolina, United States

Richard Steet,

• van Eerde, Albertien M., University Medical Center Utrecht, Department of Genetics, Utrecht, Utrecht, Netherlands

Albertien M. van Eerde,

Background

NEK8 encodes a protein that localizes to the primary cilium. Biallelic NEK8 variants are known to cause multiorgan developmental defects including renal cystic dysplasia, with heterozygous carrier parents being asymptomatic. This autosomal recessive inheritance is most common for ciliopathies. Complementary to this, we now propose a dominant-negative effect for certain heterozygous NEK8 missense variants in the kinase domain.

Methods

We performed genetic testing in patients from several medical centers. To explore the consequences of the identified NEK8 variants we are performing cilia staining assays in patients' skin fibroblast and kidney cells, as well as in mIMCD3 cells overexpressing the identified variants.

Results

We identified three distinct heterozygous NEK8 variants in eight families (table 1), all leading to missense alterations in the kinase domain. The large symptomatic family and the de novo occurrences are also in favor of a dominant mode of inheritance. All patients have a kidney phenotype, varying in severity, age of onset and presence of kidney failure. Interestingly the p.Arg45Trp variant is a recurrent variant found in six unrelated families.
Our preliminary results from functional studies show normal localization of the NEK8 protein to the Golgi region, but abnormal primary cilia formation, in serum starved patient derived cells – a finding consistent with pathogenicity.

Conclusion

We present the first evidence for a pathogenic effect of heterozygous NEK8 variants. Remarkably our patients present with a renal limited phenotype as compared to the multiorgan defects found in patients with biallelic variants. This reveals a new mode of inheritance for NEK8 variants and expands genotype-phenotype correlations for this gene.