PUBLICATION
Loss of function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish
- Authors
- Reilly, M.L., Stokman, M.F., Magry, V., Jeanpierre, C., Alves, M., Paydar, M., Hellinga, J., Delous, M., Pouly, D., Failler, M., Martinovic, J., Loeuillet, L., Leroy, B., Tantau, J., Roume, J., Evans, C.G., Shan, X., Filges, I., Allingham, J.S., Kwok, B.H., Saunier, S., Giles, R.H., Benmerah, A.
- ID
- ZDB-PUB-181103-10
- Date
- 2018
- Source
- Human molecular genetics 28(5): 778-795 (Journal)
- Registered Authors
- Delous, Marion, Saunier, Sophie
- Keywords
- none
- MeSH Terms
-
- Animals
- Congenital Abnormalities/genetics*
- Congenital Abnormalities/metabolism
- Cytokinesis/genetics
- Disease Models, Animal
- Female
- Fluorescent Antibody Technique
- Genes, Lethal
- Genetic Association Studies*/methods
- Genetic Loci
- Genetic Predisposition to Disease*
- Humans
- Kidney/abnormalities*
- Kidney/metabolism
- Kidney Diseases/congenital*
- Kidney Diseases/genetics
- Kidney Diseases/metabolism
- Kinesins/chemistry
- Kinesins/genetics*
- Kinesins/metabolism
- Loss of Function Mutation*
- Male
- Microcephaly/genetics*
- Microcephaly/metabolism
- Microcephaly/pathology
- Oncogene Proteins/chemistry
- Oncogene Proteins/genetics*
- Oncogene Proteins/metabolism
- Pedigree
- Phenotype
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 30388224 Full text @ Hum. Mol. Genet.
Citation
Reilly, M.L., Stokman, M.F., Magry, V., Jeanpierre, C., Alves, M., Paydar, M., Hellinga, J., Delous, M., Pouly, D., Failler, M., Martinovic, J., Loeuillet, L., Leroy, B., Tantau, J., Roume, J., Evans, C.G., Shan, X., Filges, I., Allingham, J.S., Kwok, B.H., Saunier, S., Giles, R.H., Benmerah, A. (2018) Loss of function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish. Human molecular genetics. 28(5):778-795.
Abstract
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 foetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses show that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human foetal 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping