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 wholeexome 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.
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We are grateful to all individuals with nephronophthisis-related ciliopathies, asphyxiating thoracic dystrophy, and Mainzer-Saldino syndrome and their family members for their participation. We further thank the investigators of the UK10K Consortium ( www.uk10k.org ) and the FORGE Canada Consortium, as well as the following funding agencies that supported this work: the Howard Hughes Medical Institute, the National Institutes of Health, the Agence Nationale de la Recherche, the Fondation pour la Recherche Médicale, the Institute National de la Santé et de la Recherche Médicale, the Imagine Institute, the Wellcome Trust, the Dutch Kidney Foundation, the European Community, the Royal Children’s Hospital Brisbane Foundation, the Newlife Foundation for Disabled Children UK, and the Action Medical Research UK. Detailed Supplemental Acknowledgments can be found in the Supplemental Data .
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