Clinical mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2

The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal deformation. Motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport in the cilium. WDR34, a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, Short-rib polydactyly syndrome or Asphyxiating thoracic dysplasia patients by stably expressing the mutant proteins in WDR34 knockout cells. WDR34 mutations led to different spectrums of phenotypes. Each mutation results in a distinct profile of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, IFT-B protein localization, transition zone integrity, and Hedgehog signaling were also affected. ### Competing Interest Statement The authors have declared no competing interest.