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Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2013 Jun 01; Vol. 22 (11), pp. 2177-85. Date of Electronic Publication: 2013 Feb 14. - Publication Year :
- 2013
-
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.
- Subjects :
- Abnormalities, Multiple pathology
Cell Line
Consanguinity
Dandy-Walker Syndrome pathology
Female
Fetus abnormalities
Gene Frequency
Genome-Wide Association Study
Genotype
Hippo Signaling Pathway
Humans
Male
NIMA-Related Kinases
Pancreatic Cyst pathology
Pedigree
Polymorphism, Single Nucleotide
Protein Binding
TRPP Cation Channels genetics
TRPP Cation Channels metabolism
Abnormalities, Multiple genetics
Abnormalities, Multiple metabolism
Dandy-Walker Syndrome genetics
Dandy-Walker Syndrome metabolism
Gene Expression Regulation
Mutation
Pancreatic Cyst genetics
Pancreatic Cyst metabolism
Protein Kinases genetics
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-myc genetics
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 22
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 23418306
- Full Text :
- https://doi.org/10.1093/hmg/ddt070