Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.DOI: http://dx.doi.org/10.7554/eLife.08077.001

cilia are complex microtubule-based organelles essential to a range of processes associated with embryogenesis and tissue homeostasis. Mutations in components of these organelles or those involved in their assembly may result in a diverse set of diseases collectively known as ciliopathies. Accordingly, many cilia-associated proteins have been described, while those distinguishing cilia subtypes are poorly defined. Here we set out to define genes associated with motile cilia in humans based on their transcriptional signature. To define the signature, we performed network deconvolution of transcriptomics data derived from tissues possessing motile ciliated cell populations. for each tissue, genes coexpressed with the motile cilia-associated transcriptional factor, FOXJ1, were identified. The consensus across tissues provided a transcriptional signature of 248 genes. To validate these, we examined the literature, databases (cilDB, centrosomeDB, ciliacarta and Syscilia), single cell RnA-Seq data, and the localisation of mRnA and proteins in motile ciliated cells. in the case of six poorly characterised signature genes, we performed new localisation experiments on ARMC3, EFCAB6, FAM183A, MYCBPAP, RIBC2 and VWA3A. in summary, we report a set of motile cilia-associated genes that helps shape our understanding of these complex cellular organelles. Cilia and flagella are related organelles that facilitate an array of cellular functions. In eukaryotes, the core structural components of cilia includes: the axoneme, a microtubular protrusion from the cell surface composed of an array of microtubules; a centrosomal core, comprised of a mother (basal body) and daughter centriole 1,2 anchored to the base of the axoneme, and the centriole-associated distal and sub-distal appendages 3. Generally, cilia can be subdivided into non-motile primary cilia, in which nine microtubules constitute the axoneme (9 + 0) and motile cilia, characterised by an additional central pair of microtubules (9 + 2) 4-6. Primary cilia are found on most cell types, where their principal role is as a sensor of the cell's microenvironment 7. In contrast, motile cilia are restricted to specific cell populations. Flagellum function as a single large 'propeller' and in eukaryotes are found exclusively on spermatocytes where they drive cell motility. Other motile cilia are found in large numbers on the apical surface of certain types of epithelial cells, where their coordinated beating displaces the luminal contents over the epithelial surface, e.g. the clearance of mucus in the respiratory tract. Whilst there are a set of core proteins common to all cilia, there are also structural and regulatory elements unique to motile cilia which underpin their distinct functional activity 8,9. Motile cilia play a vital role in human development and homeostasis, and there is a growing list of ciliopathies (cilia-related diseases) associated with mutations of ciliary assembly proteins and protein components of these organelles. These include defects in left-right patterning...

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The mutation was mapped and a candidate gene encoding LIM-domain kinase 1 () identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.