Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans

Jan Halbritter, Albane A. Bizet, Miriam Schmidts, Jonathan D. Porath, Daniela A. Braun, Heon Yung Gee, Aideen M. McInerney-Leo, Pauline Krug, Emilie Filhol, Erica E. Davis, Rannar Airik, Peter G. Czarnecki, Anna M. Lehman, Peter Trnka, Patrick Nitschké, Christine Bole-Feysot, Markus Schueler, Bertrand Knebelmann, Stéphane Burtey, Attila J. Szabó, Kálmán Tory, Paul J. Leo, Brooke Gardiner, Fiona A. McKenzie, Andreas Zankl, Matthew A. Brown, Jane L. Hartley, Eamonn R. Maher, Chunmei Li, Michel R. Leroux, Peter J. Scambler, Shing H. Zhan, Steven J. Jones, Hülya Kayserili, Beyhan Tuysuz, Khemchand N. Moorani, Alexandru Constantinescu, Ian D. Krantz, Bernard S. Kaplan, Jagesh V. Shah, UK10K Consortium, Toby W. Hurd, Dan Doherty, Nicholas Katsanis, Emma L. Duncan, Edgar A. Otto, Philip L. Beales, Hannah M. Mitchison, Sophie Saunier, Friedhelm Hildebrandt

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.