Abstract
BackgroundJoubert 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.ResultsUsing 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.ConclusionsWe 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 materialThe online version of this article (doi:10.1186/s13059-015-0858-z) contains supplementary material, which is available to authorized users.
Highlights
Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation, together with neurological symptoms of variable expressivity
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
Summary
Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. Cilia are microtubule (MT)-based structures extending from the surface of most eukaryotic cells, serving important roles in cell and fluid motility, and sensory perception. Defects in cilia underlie a wide range of human disorders, collectively called ciliopathies, characterised by a multitude of symptoms including cystic kidneys, retinal dystrophy, organ laterality defects, skeletal abnormalities, and peripheral and central nervous system defects [2]. One such disorder is Joubert syndrome (JBTS), a recessively inherited disorder affecting ~1/100,000 live births defined by hypotonia, ataxia, developmental delay, intellectual disability, episodes of neonatal fast or slow breathing, and dysmorphic facial features [3]. JBTS and related disorders overlap with other syndromic ciliopathies such as Meckel Gruber syndrome (MKS), Bardet-Biedl syndrome, nephronophthisis (NPHP) and oral-facial digital syndrome (OFD)
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