Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease

The Han:SPRD Rat: A Preclinical Model of Polycystic Kidney Disease

“…ANKS6 transports NEK8 from the cytoplasm to the cilia, where it is phosphorylated in the presence of INV and NPHP3, suggesting its role as both a substrate and a functional activator of NEK8 kinase activity [59]. NEK8 has already been identified as an important regulator in kidney and liver cystogenesis and seems to be involved in the same signaling cascade as PKD1 and PKD2 [60,61]. Moreover, a study by Nakajima et al has demonstrated that the IC functions as an intraciliary signal-generating center and that ANKS6 may be involved in the transmission of signals from cilia to the cytoplasm [62], possibly indicating that the phosphorylation status of ANKS6 influences the stability of the protein [47,62,63].…”

The dominant findings of a recessive man: from Mendel’s kid pea to kidney

“…This has nevertheless been observed in some nephropathies, like the IFT140 , NEK8 , or NPHS2 -associated ones. While their biallelic loss-of-function variants cause Mainzer-Saldino syndrome [ 16 ], renal-hepatic-pancreatic dysplasia [ 17 – 19 ], or steroid-resistant nephrotic syndrome [ 20 ], respectively, monoallelic variants of IFT140 and NEK8 were found causal in rare forms of ADPKD [ 21 – 23 ] and those of NPHS2 in focal segmental glomerulosclerosis (FSGS) [ 24 ]. The monoallelic variants were specific in NEK8 (i.e., p.R45W) [ 21 , 22 ] and in NPHS2 (p.L330Vfs*15 with a premature stop in the last exon) [ 24 ], suggesting a dominant negative effect [ 21 ], but the IFT140 variants in mild ADPKD are intriguingly loss-of-function variants [ 23 ].…”

“…While their biallelic loss-of-function variants cause Mainzer-Saldino syndrome [ 16 ], renal-hepatic-pancreatic dysplasia [ 17 – 19 ], or steroid-resistant nephrotic syndrome [ 20 ], respectively, monoallelic variants of IFT140 and NEK8 were found causal in rare forms of ADPKD [ 21 – 23 ] and those of NPHS2 in focal segmental glomerulosclerosis (FSGS) [ 24 ]. The monoallelic variants were specific in NEK8 (i.e., p.R45W) [ 21 , 22 ] and in NPHS2 (p.L330Vfs*15 with a premature stop in the last exon) [ 24 ], suggesting a dominant negative effect [ 21 ], but the IFT140 variants in mild ADPKD are intriguingly loss-of-function variants [ 23 ]. Such transformations of dominant or recessive phenotypes would have reversed the two forms of a trait in Mendel’s experiment, but would not have changed the 3:1 ratio of the dominant and recessive forms in the second generation.…”