Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Nephrology

Background:

• Cilia are crucial for cellular function, and mutations in ciliary genes cause ciliopathies, often featuring cystic kidneys.
• Ciliopathies exhibit diverse phenotypes, from mild to lethal, with kidney abnormalities being a common characteristic.

Purpose of the Study:

• To investigate the genetic basis of a severe early embryonic phenotype with cystic kidneys, liver, pancreas, and heart defects in a consanguineous family.
• To identify the specific gene mutation responsible for this ciliopathy and elucidate its functional consequences.

Main Methods:

• Genome-wide linkage analysis was performed to map the disease locus.
• A homozygous nonsense mutation in the NEK8/NPHP9 gene was identified.
• NEK8 expression levels and downstream effects on gene expression (PKD1, PKD2, c-MYC) and protein interactions (NPHP3, TAZ) were analyzed in patient-derived fibroblasts.

Main Results:

• A novel homozygous nonsense mutation in NEK8/NPHP9 was identified, leading to a complete loss of NEK8 expression in affected fetuses.
• Patient fibroblasts showed decreased expression of polycystic kidney disease genes (PKD1, PKD2) and upregulation of the oncogene c-MYC.
• NEK8 was found to interact with NPHP3 and activate the Hippo pathway effector TAZ, suggesting a role in multiple signaling pathways.

Conclusions:

• Complete loss of NEK8 function causes a severe early embryonic ciliopathy characterized by cystic kidneys and developmental defects.
• NEK8 is essential for normal organ development, and its absence perturbs critical signaling pathways including those involving NPHP3 and TAZ.
• This study expands the spectrum of NEK8-related disorders and highlights its vital role in embryonic development.