Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome.
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 intraflagellar (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 modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These findings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS.
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.|Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), University of Malaga, Malaga, 29071, Spain.
Ivan
I
Duran
Department of Human Genetics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.
S Paige
SP
Taylor
Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, California, 90095, USA.
Wenjuan
W
Zhang
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.
Jorge
J
Martin
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.
Kimberly N
KN
Forlenza
Children's Healthcare of Atlanta, Atlanta, GA, 30342, USA.
Rhonda P
RP
Spiro
University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, 98195, USA.
Deborah A
DA
Nickerson
University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, 98195, USA.
Michael
M
Bamshad
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.|Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, California, 90095, USA.
Daniel H
DH
Cohn
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.|Department of Human Genetics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California, 90095, USA.
Deborah
D
Krakow
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