title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects.
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.
authors.affiliation: Clinical Genetics, Children's University Hospital, Temple Street, Dublin 1, Ireland, UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, jillian.casey@ucd.ie.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Casey
authors.affiliation: UCD School of Biomolecular & Biomedical Science, Conway Institute.
authors.forename: Kieran
authors.initials: K
authors.lastname: Brennan
authors.affiliation: UCD School of Biomolecular & Biomedical Science, Conway Institute.
authors.forename: Noemie
authors.initials: N
authors.lastname: Scheidel
authors.affiliation: UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, UCD School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: McGettigan
authors.affiliation: UCD School of Biomolecular & Biomedical Science, Conway Institute.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Lavin
authors.affiliation: UCD School of Biomolecular & Biomedical Science, Conway Institute.
authors.forename: Stephen
authors.initials: S
authors.lastname: Carter
authors.affiliation: UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences.
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.affiliation: North West Thames Regional Genetics Service, Northwick Park Hospital, London North West Healthcare NHS Trust, Watford Road, Harrow HA1 3UJ, UK, Leicestershire Genetics Service, Leicester Royal Infirmary, Leicester LE1 5WW, UK, St Peter's College, University of Oxford, Oxford OX1 2DL, UK and.
authors.forename: Huw
authors.initials: H
authors.lastname: Dorkins
authors.affiliation: North West Thames Regional Genetics Service, Northwick Park Hospital, London North West Healthcare NHS Trust, Watford Road, Harrow HA1 3UJ, UK.
authors.forename: Neeti
authors.initials: N
authors.lastname: Ghali
authors.affiliation: UCD School of Biomolecular & Biomedical Science, Conway Institute.
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Blacque
authors.affiliation: UCD School of Biomolecular & Biomedical Science, Conway Institute.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Mc Gee
authors.affiliation: Manchester Academic Health Science Centre, Genetic Medicine-University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Murphy
authors.affiliation: Clinical Genetics, Children's University Hospital, Temple Street, Dublin 1, Ireland, UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences.
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D002923:Cilia / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D000072379:NIMA-Related Kinases / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000209:etiology* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C462119:NEK9 protein, human; D000072379:NIMA-Related Kinases