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KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome
- Source :
- Genome Biology, Genome Biology, 16, 1, pp. 293, Genome Biology, 16, 293
- Publication Year :
- 2015
- Publisher :
- BioMed Central, 2015.
-
Abstract
- Background Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures. Results Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556-/- null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions. Conclusions We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0858-z) contains supplementary material, which is available to authorized users.
- Subjects :
- Adult
Male
K04F10.2
KIAA0556
Microtubule
Microtubules
Retina
Mice
Joubert syndrome
Cerebellum
Animals
Humans
Abnormalities, Multiple
Exome
Cilia
Eye Abnormalities
Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12]
Caenorhabditis elegans
Child
Cells, Cultured
Adenosine Triphosphatases
ADP-Ribosylation Factors
Research
Brain
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]
Kidney Diseases, Cystic
Basal Bodies
Pedigree
Mice, Inbred C57BL
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
Basal body
Child, Preschool
Mutation
Female
Katanin
Microtubule-Associated Proteins
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 1474760X and 14747596
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Genome Biology
- Accession number :
- edsair.pmid.dedup....3a03be327138e2a6b4b65d2f131eddee