Journal Article


Sally Ann Lynch
Helen Murphy
Margaret M Mc Gee
Oliver E Blacque
Neeti Ghali
Huw Dorkins
Sean Ennis
Stephen Carter
Paul T Lavin
Paul McGettigan
and 3 others



functional characterization cell proliferation cell cycle progression protein expression cell cycle protein localization caenorhabditis elegans nucleotide mapping

Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects. (2015)

Abstract Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. Whilst >450 skeletal dysplasias have been reported, 30% are genetically uncharacterized. We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen. Single nucleotide polymorphism homozygosity mapping and whole exome sequencing identified a novel homozygous stop-gain mutation in NEK9 (c.1489C>T; p.Arg497*) as the cause of this disorder. NEK9 encodes a never in mitosis gene A-related kinase involved in regulating spindle organization, chromosome alignment, cytokinesis and cell cycle progression. This is the first disorder to be associated with NEK9 in humans. Analysis of NEK9 protein expression and localization in patient fibroblasts showed complete loss of full-length NEK9 (107 kDa). Functional characterization of patient fibroblasts showed a significant reduction in cell proliferation and a delay in cell cycle progression. We also provide evidence to support possible ciliary associations for NEK9. Firstly, patient fibroblasts displayed a significant reduction in cilia number and length. Secondly, we show that the NEK9 orthologue in Caenorhabditis elegans, nekl-1, is almost exclusively expressed in a subset of ciliated cells, a strong indicator of cilia-related functions. In summary, we report the clinical and molecular characterization of a lethal skeletal dysplasia caused by NEK9 mutation and suggest that this disorder may represent a novel ciliopathy.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Sally Ann Lynch, Helen Murphy, Margaret M Mc Gee, Oliver E Blacque, Neeti Ghali, Huw Dorkins, Sean Ennis, Stephen Carter, Paul T Lavin, Paul McGettigan and 3 others

Experts in our system

Sally Ann Lynch
University College Dublin
Total Publications: 32
Oliver E Blacque
University College Dublin
Total Publications: 26
Sean Ennis
University College Dublin
Total Publications: 52
Paul A. McGettigan
University College Dublin
Total Publications: 46