NEK8 – Renal-Hepatic-Pancreatic Dysplasia 2

Biallelic variants in NEK8 (Never in mitosis A-related Kinase 8) have been reported in five probands from two unrelated families with renal-hepatic-pancreatic dysplasia 2 (RHPD2). Exome sequencing in two affected brothers identified compound heterozygous variants, including a frameshift c.2069_2070insC (p.Ter693LeufsTer86) and a missense c.1043C>T (p.Thr348Met), segregating with disease in an autosomal recessive manner (PMID:26697755). A previous report described three fetuses from a single family with RHPD2 harboring biallelic NEK8 variants, confirming multi-organ involvement and significant intra-familial expressivity (PMID:26697755). No recurrent or founder alleles have been described to date, and carrier frequency data remain unavailable.

Functional studies demonstrate that NEK8 is critical for ciliary and centrosomal integrity. The murine jck model bearing Nek8 mutations develops autosomal recessive juvenile cystic kidney disease, with abnormal actin cytoskeleton and enlarged renal epithelial cells, while zebrafish morpholino knockdown of nek8 yields pronephric cysts, together supporting a loss-of-function mechanism in renal tissue context (PMID:12421721). Additional cellular assays reveal that NEK8 localizes to the RCC1 domain at centrosomes and cilia, mediating centrosome recruitment and ciliary function. These data align with the hepatic and pancreatic anomalies seen in human RHPD2, reflecting the role of NEK8 in multi-organ ciliogenesis. Further studies are needed to fully delineate genotype–phenotype correlations and to assess pathogenicity of rare missense alleles.

Key Take-home: Biallelic NEK8 loss-of-function and missense variants cause autosomal recessive RHPD2, supporting NEK8 sequencing in syndromic ciliopathy evaluation.

References

• American journal of medical genetics. Part A • 2016 • Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies. PMID:26697755
• Development (Cambridge, England) • 2002 • A defect in a novel Nek-family kinase causes cystic kidney disease in the mouse and in zebrafish. PMID:12421721

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