Kidney Week

Abstract: SA-PO583

Functional Analysis of a De Novo Monoallelic NEK8 Variant Supports Pathogenicity for a Polycystic Kidney Disease Phenotype

Session Information

• Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Thompson, Whitney, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Whitney Thompson, MD

• Chen, Chuan, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Chuan Chen, PhD

• Yang, Hana, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Hana Yang, PhD

• Baker, Tracy A., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Tracy A. Baker

• Cramer, Carl H., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Carl H. Cramer, MD

• Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Ling, Kun, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Kun Ling, PhD

• Hanna, Christian, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Christian Hanna, MD, MS

Background

While PKD1 and PKD2 pathogenic variants are most common in ADPKD, additional genes linked to primary cilia are increasingly recognized in ADPKD. One such gene, NEK8, encodes a ciliary serine/threonine kinase involved in renal and cardiovascular development. Biallelic pathogenic variants in NEK8 cause renal-hepatic-pancreatic dysplasia-2; however, certain monoallelic NEK8 variants have been recently linked to ADPKD, causing phenotypes ranging from childhood-onset kidney failure to typical ADPKD. Decreased polycystin-2 (PC2) in cilia have been reported in Nek8 null cells. Herein, we report studies on a novel monoallelic NEK8 variant (c.463A>G, p.Ser155Gly) in a pediatric patient.

Methods

Genetics and the clinical phenotype were characterized and the NEK8 variant was stably expressed in Nek8 null cells. The ciliary biogenesis, protein composition, and Hedgehog (Hh) signaling were compared between the empty vector (Mock), the Myc-tagged NEK8 wild type (WT), and NEK8 (p.Ser155Gly).

Results

A 12-year-old male was diagnosed incidentally with bilateral medullary kidney cysts. PKD panel screening found a de novo NEK8 variant of uncertain significance (VUS), c.463A>G (p.Ser155Gly), as the most likely pathogenic change. This NEK8 variant localizes to cilia and supports ciliogenesis and cilia length to the same extent as the WT (Fig 1a). Yet, the ciliary signals of ANSK6 and PC2 are reduced in cells expressing the NEK8 variant (Fig 1b, c). In NEK8 variant cilia, SAG weakly activated the Hh pathway compared to WT cilia, inducing less ciliary accumulation of Gli3 and Smoothened (Smo) (Fig 1d).

Conclusion

Functional analysis supports the pathogenicity of our patient’s NEK8 VUS. Monoallelic NEK8 should be considered in childhood ADPKD cases.

Funding

• Other U.S. Government Support