Loss-of-function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish.

Autor:	Reilly ML; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France.; Paris Diderot University, Department of Life Sciences, Paris, France., Stokman MF; Department of Genetics, University Medical Center Utrecht, Utrecht University, JE Utrecht, Netherlands., Magry V; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Jeanpierre C; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Alves M; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Paydar M; Institute for Research in Immunology and Cancer, Département de médecine, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC, Canada., Hellinga J; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada., Delous M; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Pouly D; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Failler M; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Martinovic J; Unit of Fetal Pathology, Antoine Béclère Hospital, AP-HP, Clamart, France.; INSERM U-788, Génétique/Neurogénétique, 94270 Le Kremlin-Bicêtre, France., Loeuillet L; Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Leroy B; Service d'Anatomie et de Cytologie Pathologiques, Centre hospitalier intercommunal de Poissy, Saint Germain en Laye, France., Tantau J; Service d'Anatomie et de Cytologie Pathologiques, Centre hospitalier intercommunal de Poissy, Saint Germain en Laye, France., Roume J; Service de Génétique, Centre hospitalier intercommunal de Poissy, 78100 Saint Germain en Laye, France., Gregory-Evans CY; Department of Ophthalmology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada., Shan X; Department of Ophthalmology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada., Filges I; Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital of Basel, University of Basel, Basel, Switzerland.; Department of Clinical Research, University Hospital of Basel, University of Basel, Basel, Switzerland.; Department of Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada., Allingham JS; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada., Kwok BH; Institute for Research in Immunology and Cancer, Département de médecine, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC, Canada., Saunier S; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France., Giles RH; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, 3512 JE Utrecht, Netherlands., Benmerah A; Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, Paris, France.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2019 Mar 01; Vol. 28 (5), pp. 778-795.
DOI:	10.1093/hmg/ddy381
Abstrakt:	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. (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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