TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

Abstract

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

Utilizing the chicken as an animal model for human craniofacial ciliopathies

“…Despite the situs of the viscera and turning/patterning of the heart tube being normal (Stephen et al, 2014), the anatomy of the ta 3 body is severely dysmorphic. The ta 3 body axis is shortened (Stephen et al, 2015), the lungs are hypoplastic and the liver is fibrotic and cholestatic (Davey et al, 2014). Skeletogenesis is aberrant (Macrae et al, 2010), embryos exhibit unusual vascular abnormalities (Davey et al, 2007) and development and differentiation of the central nervous system is impaired (Buxton et al, 2004; Stephen et al, 2013).…”

“…The KIAA0586 protein, eventually named TALPID3, was isolated in an early centrosomal proteome analysis (Andersen et al, 2003) and was confirmed to be a centrosomal protein (Yin et al, 2009) that normally localized in a ring at the distal end of the basal body (Kobayashi et al, 2014). The TALPID3 protein was shown to be required for docking of the basal body to the cell surface (Yin et al, 2009) prior to ciliogenesis (Kobayashi et al, 2014) and has also been implicated in centrosome migration (Stephen et al, 2013), control of centrosome length (Stephen et al, 2015) and formation of centriolar satellites (Kobayashi et al, 2014). Loss of the TALPID3 protein, in various model species, resulted in a loss of cilia (Bangs et al, 2011; Ben et al, 2011; Yin et al, 2009), both non-motile and motile (Stephen et al, 2013).…”

“…Several groups have used the ta 3 limb to determine that there was a decrease in cell death, changes in cell proliferation, abnormal cell adhesiveness and migration during limb development (Ede and Agerbak, 1968; Francis-West et al, 1995; Hinchliffe and Ede, 1967; Hinchliffe and Thorogood, 1974; Izpisua-Belmonte et al, 1992). Furthermore, there was a general loss of polarity in both the cell and developing tissues (Stephen et al, 2015). Cell differentiation was also affected, particularly during skeletal development.…”

Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome

“…Homozygous occurrence of this variant in healthy individuals was assumed to ‘either be due to protective modifiers or a low mutational load in the ciliome of the respective person’ 6. Based on the frequency data of 0.003117 for the c.428delG variant obtained from the gnomAD database—which also includes two homozygous carriers—we conclude that the c.428delG variant likely represents a mild hypofunctional allele, which is not disease causing in a homozygous situation.…”

“…The putative conflicting observation of homozygosity of the KIAA0586 c.428delG variant in both, patients with JBTS and healthy individuals, was discussed previously 6. Homozygous occurrence of this variant in healthy individuals was assumed to ‘either be due to protective modifiers or a low mutational load in the ciliome of the respective person’ 6.…”