KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome

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.

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

“…However, in addition to the core Joubert features, both of our patients had growth hormone deficiency in association with structural abnormalities of the pituitary gland on brain MRI. Growth hormone deficiency occurs in a small number of patients with ciliopathies, including a family recently reported with KIAA0556 mutations (Parisi and Glass 1993; Sanders et al 2015), and an IFT172-related disorder (Lucas-Herald et al 2015), suggesting the potential importance of ciliary function in the development of the pituitary gland. Whether the pituitary defects in our patients were caused by the KIAA0753 defect remains uncertain; identification of other Joubert syndrome patients with defects in KIAA0753 will help to answer this question.…”

Inferring the Evolutionary History of Your Favorite Protein: A Guide for Molecular Biologists

“…This way, evolutionary analyses also contribute to human health, since they may characterize disease‐associated proteins through their ortholog in model organisms such as Caenorhabditis elegans ( C. elegans ). For example, the worm ortholog of human protein KIAA0556, associated with Joubert syndrome, was shown to operate in the cilium, allowing in‐depth molecular characterization of this protein's cellular function. Another frequently asked question is which residues are conserved and therefore likely functionally important?…”

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

“…According to a recent study, about 55%~60% patients with Joubert syndrome are caused by the known gene mutations [62]. To date, there are about 30 genes to be associated with Joubert syndrome or Joubert syndrome related disorders (NPHP1, AHI1, ARMC9, CEP290, RPGRIP1L, TMEM67, CC2D2A, ARL13B, INPP5E, OFD1, TMEM216, CEP41, TMEM237, TCTN2, KIAA0556, KIF7, TCTN1, TMEM138, MKS1, C5ORF42, TMEM231, TCTN3, CSPP1, PDE6D, IFT172, ZNF423, TTC21B, B9D1, B9D2, and C2CD3) by target sequencing [63][64][65], indicating genetic heterogeneity of Joubert syndrome to a large extent.…”