Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 5, Pages 915-925Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.09.012
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Funding
- Howard Hughes Medical Institute
- National Institutes of Health
- Agence Nationale de la Recherche
- Fondation pour la Recherche Medicale
- Institute National de la Sante et de la Recherche Medicale
- Imagine Institute
- Wellcome Trust
- Dutch Kidney Foundation
- European Community
- Royal Children's Hospital Brisbane Foundation
- Newlife Foundation for Disabled Children UK
- Action Medical Research UK
- Action Medical Research [1794] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
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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.
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