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

UK10K Consortium, 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 BurteyAttila 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, Toby W Hurd, Dan Doherty, Nicholas Katsanis, Emma L Duncan, Edgar A Otto, Philip L Beales, Hannah M Mitchison, Sophie Saunier, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)915-25
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 7 Nov 2013


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