1 Scientific RepoRts | 6:34232 | DOI: 10.1038/srep34232 www.nature.com/scientificreports Destabilization of the IFt-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short- Rib Polydactyly Syndrome Ivan Duran 1,2 , S. Paige taylor 3 , Wenjuan Zhang 4 , Jorge Martin 1 , Kimberly N. Forlenza 1 , Rhonda P. Spiro 5 , Deborah A. Nickerson 6 , Michael Bamshad 6 , Daniel H. Cohn 1,4 & Deborah Krakow 1,3,7 Short-rib polydactyly syndromes (SRPS) and Asphyxiating thoracic dystrophy (ATD) or Jeune Syndrome are recessively inherited skeletal ciliopathies characterized by profound skeletal abnormalities and are frequently associated with polydactyly and multiorgan system involvement. SRPS are produced by mutations in genes that participate in the formation and function of primary cilia and usually result from disruption of retrograde intrafagellar (IFT) transport of the cilium. Herein we describe a new spectrum of SRPS caused by mutations in the gene IFT81, a key component of the IFT-B complex essential for anterograde transport. In mutant chondrocytes, the mutations led to low levels of IFT81 and mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modifcation of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These fndings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS. Asphyxiating thoracic dystrophy (ATD) and the short rib polydactyly syndromes (SRPS) are autosomal reces- sively inherited skeletal disorders and are categorized as ciliopathies with major skeletal involvement 1,2 . Both are characterized by a long narrow chest that causes varying degree of respiratory distress, from minor insufciency to respiratory failure and death. Skeletal features include short ribs, micromelia (shortened tubular bones), abnor- mal shaped roof of the acetabulum (trident-shaped) and frequently polydactyly. Non-skeletal features include retinal degeneration, and renal, pancreatic and liver abnormalities 3,4 . ATD can be milder and many individu- als survive into young adulthood. Mutations in several genes have been associated with this phenotypic spec- trum and include DYNC2H1 [OMIM 603297], DYNC2LI1, NEK1 [OMIM 604588], IFT140 [OMIM 614620], EVC1 [OMIM 604831], EVC2 [OMIM 607261], KIAA0586 [OMIM 610178], CEP120 [OMIM 613446], WDR19 [OMIM 608151], WDR34 [OMIM 613363], WDR35 [OMIM 613602], WDR60 [OMIM 615462], TTC21B [OMIM 612014], IFT172 [OMIM 607386] and IFT80 [OMIM 611177] 5–20 . Many of the proteins encoded by the aforementioned genes participate in intrafagellar transport (IFT) in primary cilia, a sensory organelle present in most tissues and essential for specifc signaling pathways. Ciliary structure and function depends on bidi- rectional transport (anterograde and retrograde) that mobilizes molecules from the base of the cilia to the tip and back. Each direction uses a diferent motor system for transport, kinesins for anterograde and dyneins for retrograde 21–23 . Tese motor systems bind IFT-B and IFT-A complexes, respectively, which mediate the intake 1 Department of Orthopaedic Surgery, David Gefen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA. 2 Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), University of Malaga, Malaga, 29071, Spain. 3 Department of Human Genetics, David Gefen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA. 4 Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, California, 90095, USA. 5 Children’s Healthcare of Atlanta, Atlanta, GA, 30342, USA. 6 University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, 98195, USA. 7 Department of Obstetrics and Gynecology, David Gefen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA. Correspondence and requests for materials should be addressed to D.K. (email: dkrakow@mednet.ucla.edu) Received: 01 June 2016 Accepted: 06 September 2016 Published: 26 September 2016 opeN