1. Loss-of-function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish
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Daniel Pouly, Laurence Loeuillet, Joelle Roume, Xianghong Shan, Sophie Saunier, Alexandre Benmerah, Marion Failler, Marijn Stokman, Brigitte Leroy, Jelena Martinovic, Mohammadjavad Paydar, Isabel Filges, Virginie Magry, Marine Alves, Cheryl Y. Gregory-Evans, Benjamin H. Kwok, Marion Delous, John S. Allingham, Madeline Louise Reilly, Julia Tantau, Jacqueline R. Hellinga, Rachel H. Giles, Cécile Jeanpierre, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Utrecht University [Utrecht], Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), Queen's University [Kingston, Canada], Service de foetopathologie [Béclère], Université Paris-Sud - Paris 11 (UP11)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomie et de Cytologie Pathologiques [Poissy], CHI Poissy-Saint-Germain, Service de génétique [Poissy], University of British Columbia (UBC), University of Basel (Unibas), University Medical Center [Utrecht], This work was supported by the Fondation pour la Recherche Médicale (DEQ20130326532 to SS), the European Union’sSeventh Framework Programme (FP7/2007–2013) grant 305608 (EURenOmics, CJ), the GIS-Institut desMaladies Rares (AMA11025KSA to CJ and SS), the CIHR, NSERC, CCSRI, and FRQS (BK), the SwissNational Science Foundation (SNSF, IF), the Dutch Kidney Foundation KOUNCIL consortium(CP11.18). The Imagine Institute is supported by an ANR grant (ANR-A0-IAHU-01)., European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), Université Paris-Sud - Paris 11 (UP11)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Benmerah, Alexandre, and European Consortium for High-Throughput Research in Rare Kidney Diseases - EURENOMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305608 - VALID
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0301 basic medicine ,Male ,Microcephaly ,Fluorescent Antibody Technique ,Kinesins ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Kidney ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Ciliopathies ,0302 clinical medicine ,Loss of Function Mutation ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Zebrafish ,Genetics (clinical) ,Oncogene Proteins ,biology ,Cilium ,General Medicine ,Cell biology ,Pedigree ,Midbody ,Phenotype ,Female ,Kidney Diseases ,General Article ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Congenital Abnormalities ,03 medical and health sciences ,Structure-Activity Relationship ,Ciliogenesis ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Molecular Biology ,Genetic Association Studies ,Cytokinesis ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Kidney metabolism ,medicine.disease ,biology.organism_classification ,[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Disease Models, Animal ,030104 developmental biology ,Genetic Loci ,Genes, Lethal ,030217 neurology & neurosurgery - Abstract
International audience; Mutations in KIF14 have previously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Syndromic microcephaly-RHD was strongly reminiscent of clinical ciliopathies, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells. KIF14 encodes a mitotic kinesin, which plays a key role at the midbody during cytokinesis and has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with fetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses showed that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human fetal tissues further revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips indicating a shared function of KIF14 during brain and kidney development. Subsequently, analysis of a kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos, supporting a potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.
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- 2018