Mutations affecting the integrity and function of cilia have been identified in various genes over the last decade accounting for a group of diseases called ciliopathies. Ciliopathies display a broad spectrum of phenotypes ranging from mild manifestations to lethal combinations of multiple severe symptoms and most of them share cystic kidneys as a common feature. Our starting point was a consanguineous pedigree with three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas and developmental heart disease. By genome-wide linkage analysis, we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9 that encodes a kinase involved in ciliary dynamics and cell cycle progression. Missense mutations in NEK8/NPHP9 have been identified in juvenile cystic kidney jck mice and in patients suffering from nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay. In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype. We furthermore linked NEK8 with NPHP3, another NPH protein known to cause a very similar phenotype in case of null mutations. Both proteins interact and activate the Hippo effector TAZ. Taken together, our study demonstrates that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype.

Nephronophthisis (NPH) is a genetically heterogenous kidney disease and represents the most common genetic cause for end-stage renal disease in children. It is caused by the mutation of genes encoding for the nephrocystin proteins (NPHPs) which localize to primary cilia or centrosomes, classifying this disease as a 'ciliopathy'. Recently, it has been shown that NPHP4 acts as a potent negative regulator of mammalian Hippo signalling by interacting with the Lats protein kinase and controlling the phosphorylation of the oncogenic transcriptional activator TAZ. Here, we demonstrate that NPHP9, another NPH family member, also controls TAZ activity by a distinct mechanism. NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex. Binding of NPHP9 to TAZ was enhanced in a TAZ mutant that lost its ability to bind 14-3-3, suggesting that 14-3-3 and NPHP9 may compete for TAZ binding, with 14-3-3 favouring cytoplasmic retention and NPHP9 mediating nuclear delivery. Consistently, co-expression of NPHP4, which inhibits TAZ phosphorylation at the 14-3-3 binding site through the inhibition of Lats kinase activity, induced efficient nuclear delivery of the TAZ/NPHP9 protein pair. Consistent with a role for TAZ in controlling proliferation and tumorigenesis, the downregulation of NPHP9 inhibited the TAZ-dependent proliferation of hippo-responsive normal epithelial and also breast cancer cells. As NPHP9 has been shown to be upregulated in breast cancer, these data do not only support a critical role for TAZ/hippo signalling in the pathogenesis of NPH but may also imply a possible role for NPHP9 in TAZ-mediated tumorigenesis.

Overall renal cortex volumetry seems to be the most accurate technique for the evaluation of predonation SRF and allows a reliable prediction of donor's PDKF.

Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse.