Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy

Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

The role of hedgehog signalling in skeletal health and disease

“…78,79 A general role for hedgehog signalling in osteoblasts is suggested by conditions caused by mutations in genes whose protein products are required for ciliary func tion. Patients with Jeune asphyxiating thoracic dys tro phy, which is caused by a mutation in IFT80 ( encoding intraflagellar transport protein 80 homologue, a protein that inhibits cilia function) 80 have decreased hedgehog signalling in bone as well as decreased bone density. 80 IFT80 deficiency inhibits osteoblast formation, 81 and in vitro studies show that overexpression of GLI2 can rescue this defect in osteoblast differentiation.…”

“…Patients with Jeune asphyxiating thoracic dys tro phy, which is caused by a mutation in IFT80 ( encoding intraflagellar transport protein 80 homologue, a protein that inhibits cilia function) 80 have decreased hedgehog signalling in bone as well as decreased bone density. 80 IFT80 deficiency inhibits osteoblast formation, 81 and in vitro studies show that overexpression of GLI2 can rescue this defect in osteoblast differentiation. 81 Exces sive activation of hedgehog signalling in mature osteoblasts can also cause severe reduction of bone mass.…”

Subunit composition of the human cytoplasmic dynein-2 complex

“…Recent work from several groups has shown that mutations in the human orthologs of FAP133 (WDR34) and FAP163 (WDR60) cause skeletal ciliopathies (Huber et al, 2013; McInerney-Leo et al, 2013; Schmidts et al, 2013a). Although these data are consistent with WDR34 and possibly WDR60 being key components of human dynein-2, biochemical data validating this are lacking.…”

Evolución clínica, radiológica y auxológica a largo plazo de 8 niños con displasia torácica asfixiante

“…[5][6][7][8] No encontramos, en nuestro grupo, pacientes con polidactilia, descrita en el 14%. 3 Ocho niños (6 varones) con diagnóstico de displasia torácica asfixiante.…”

“…La herencia es autosómica recesiva, con considerable variabilidad en su expresión y heterogeneidad genética. 1,[3][4][5][6][7][8] El diagnóstico se realiza según criterios clínicos y radiológicos. 9 Se caracteriza por baja estatura, miembros cortos, braquidactilia, polidactilia.…”