Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the "molar tooth sign" on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.
Bibliographical noteFunding Information:
We thank the Marshfield Clinic Research Foundation and the US National Heart, Lung, and Blood Institute for genotyping support; the UCSD Neurosciences Microscopy Core for imaging (P30 NS047101); Jeong-Soo Lee (Dana Farber Cancer Institute) for the zebrafish arl13b clone; Mark Lawson (UCSD) for help with SigmaPlot and statistical analysis; Daniel O'Connor (UCSD) for control DNA samples; and members of the Gleeson laboratory for helpful discussions. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number N01-HG-65403. F.H. is supported by NIH grants R01-DK068306, R01-DK064614, and R01-DK069272 and is a Doris Duke Distinguished Clinical Scientist. V.C. was supported by a French Foundation for Medical Research (FRM) fellowship. S.L.B. was supported by the Neuroplasticity of Aging Postdoctoral Training Grant (T32 AG00216). J.Y.B. was supported by the Irvington Institute Fellowship Program of the Cancer Research Institute. This work was supported by grants from the US National Institute of Neurological Disease and Stroke, the Simons Foundation, and the Burroughs Wellcome Fund Award in Translational Research (to J.G.G.). The authors report no conflict of interest.