title: Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.
abstract: 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.
authors: Center for Human Genetics, Bioscientia, Ingelheim 55218, Germany.
authors: Valeska
authors: V
authors: Frank
authors: Sandra
authors: S
authors: Habbig
authors: Malte P
authors: MP
authors: Bartram
authors: Tobias
authors: T
authors: Eisenberger
authors: Hermine E
authors: HE
authors: Veenstra-Knol
authors: Christian
authors: C
authors: Decker
authors: Reinder A C
authors: RA
authors: Boorsma
authors: Heike
authors: H
authors: Göbel
authors: Gudrun
authors: G
authors: Nürnberg
authors: Anabel
authors: A
authors: Griessmann
authors: Mareike
authors: M
authors: Franke
authors: Lori
authors: L
authors: Borgal
authors: Priyanka
authors: P
authors: Kohli
authors: Linus A
authors: LA
authors: Völker
authors: Jörg
authors: J
authors: Dötsch
authors: Peter
authors: P
authors: Nürnberg
authors: Thomas
authors: T
authors: Benzing
authors: Hanno J
authors: HJ
authors: Bolz
authors: Colin
authors: C
authors: Johnson
authors: Erica H
authors: EH
authors: Gerkes
authors: Bernhard
authors: B
authors: Schermer
authors: Carsten
authors: C
authors: Bergmann
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D003241:Consanguinity; D003616:Dandy-Walker Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005333:Fetus / Q000002:abnormalities; D005786:Gene Expression Regulation; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D009154:Mutation; D000072379:NIMA-Related Kinases; D010181:Pancreatic Cyst / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D000072379:NIMA-Related Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D050396:TRPP Cation Channels; C458529:NEK8 protein, human