PUBLICATION
Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion
- Authors
- Dupont, M.A., Humbert, C., Huber, C., Siour, Q., Guerrera, I.C., Jung, V., Christensen, A., Pouliet, A., Garfa-Traore, M., Nitschké, P., Injeyan, M., Millar, K., Chitayat, D., Shannon, P., Girisha, K.M., Shukla, A., Mechler, C., Lorentzen, E., Benmerah, A., Cormier-Daire, V., Jeanpierre, C., Saunier, S., Delous, M.
- ID
- ZDB-PUB-190507-5
- Date
- 2019
- Source
- Human molecular genetics 28(16): 2720-2737 (Journal)
- Registered Authors
- Delous, Marion, Dupont, Marie, Saunier, Sophie
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Animals, Genetically Modified
- Carrier Proteins/chemistry
- Carrier Proteins/genetics*
- Carrier Proteins/metabolism
- Centrosome/metabolism*
- Child
- Child, Preschool
- Cilia/metabolism
- Consanguinity
- DNA Mutational Analysis
- Exome Sequencing
- Female
- Genetic Association Studies*
- Genetic Predisposition to Disease*
- Genotype
- Homozygote
- Humans
- Infant
- Male
- Microtubules/metabolism*
- Mutation*
- Pedigree
- Phenotype
- Protein Binding
- Protein Interaction Domains and Motifs/genetics
- Trimethoprim, Sulfamethoxazole Drug Combination/metabolism
- Zebrafish
- PubMed
- 31042281 Full text @ Hum. Mol. Genet.
Citation
Dupont, M.A., Humbert, C., Huber, C., Siour, Q., Guerrera, I.C., Jung, V., Christensen, A., Pouliet, A., Garfa-Traore, M., Nitschké, P., Injeyan, M., Millar, K., Chitayat, D., Shannon, P., Girisha, K.M., Shukla, A., Mechler, C., Lorentzen, E., Benmerah, A., Cormier-Daire, V., Jeanpierre, C., Saunier, S., Delous, M. (2019) Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. Human molecular genetics. 28(16):2720-2737.
Abstract
Mutations in genes encoding components of the intraflagellar transport IFT complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome (Girisha et al, 2016) leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localised with centrin at the distal end of centrioles, where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52-/- cells. Altogether, our findings allow a better comprehensive genotype-phenotype correlation amongst IFT52-related cases and revealed a novel, extra-ciliary role for IFT52 which disruption may contribute to pathophysiological mechanisms.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping