Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome

Abstract

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.

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

“…The data also establish the molecular basis of SRPS type IV and demonstrate that it is allelic with SRPS type II. Previous publications of SRPS and ATD cases from the ISDR have included 22 additional families with mutations in nine ciliary genes ( DYNC2H1, WDR34, IFT52, ICK, INTU, IFT81, DYNC2LI1, IFT43 , and WDR35 ), including six genes not represented among the current set of families (Duran, et al., ; Huber et al., ; Taylor et al., ; Taylor et al., ; Toriyama et al., ; Zhang et al., ). Mutations have also been reported in families in this spectrum of disease in six additional genes, C21ORF2 (McInerney‐Leo et al., ; Wheway et al., ), TCTEX1D2 (Gholkar et al., ), IFT172 (Halbritter et al., ), KIAA0586 (Alby et al., ), CEP120 (Shaheen et al., ), or IFT122 (Walczak‐Sztulpa et al., ), bringing the number of known skeletal ciliopathy genes to twenty six.…”

“…We identified causal variants in only six out of 152 families and only two of the 14 genes ( TRAF3IP1 and IFT80 ) that encode IFT‐B components. In the total ISDR skeletal ciliopathy cohort, there was also one family with unclassified SRPS due to IFT52 mutations (Zhang et al., ) and one family each with ATD and SRPS type III due to IFT81 mutations (Duran, et al., ), so overall nine out of 175 (5%) families studied had IFT‐B defects. It is unclear why the genes encoding anterograde IFT components are less frequently mutated than retrograde molecules in the SRPS‐ATD spectrum of disease.…”

“…Among the ciliopathy disorders, only a subset have a primary effect on the skeleton, suggesting that the proteins encoded by the skeletal ciliopathy loci have particularly important roles in the function of primary cilia in chondrocytes (Scherft & Daems, ), but exactly why the skeleton is so severely affected remains unknown. Defective sonic hedgehog signaling during skeletal pattern formation appears to be the mechanism underlying polydactyly, and disruption of proper Hh signaling has been observed in SRPS fibroblasts (Duran, et al., ; Taylor et al., ). Altered Indian hedgehog signaling is likely to be responsible in part for the defects in endochondral ossification that result in structural alterations of the growth plate and defective bone growth.…”

“…Mutations in all six of the genes encoding retrograde transport (IFT‐A) components ( IFT43 (Arts et al., ), WDR19 (Bredrup, et al., ), IFT122 (Walczak‐Sztulpa et al., ), TTC21B (Davis et al., ), WDR35 (Mill et al., ), and IFT140 (Perrault et al., ; Schmidts et al., )) have also been characterized in these disorders. By contrast, mutations in only a subset of the genes encoding IFT‐B complex members, IFT80 (Cavalcanti et al., ), IFT172 (Halbritter et al., ), IFT52 (Zhang et al., ), and IFT81 (Duran, et al., ), have been identified among the skeletal ciliopathies. In addition, mutations in two genes ( EVC (Ruiz‐Perez et al., ), EVC2 (Galdzicka et al., )) that encode basal body proteins, the NEK1 kinase gene (Thiel et al., ) and the gene encoding its interacting protein C21ORF2 (McInerney‐Leo et al., ; Wheway et al., ), the ICK MAP‐like kinase gene (Taylor et al., ), the INTU planar cell polarity (PCP) gene (Toriyama et al., ), the KIAA0586 (Alby et al., ) centrosomal protein gene, and the CEP120 core centriolar protein gene (Shaheen et al., ) have also been reported.…”

Binding of IFT22 to the intraflagellar transport complex is essential for flagellum assembly

“…Although no patient mutations in IFT22 have been reported to date, a recent study identified a series of mutations in IFT81 causing Short-Rib Polydactyly Syndrome (SRPS) (Duran et al, 2016). One of the disease mutations reported was an in-frame deletion of amino acid L435, which corresponds to L443 in trypanosomes and is a well-conserved residue positioned directly in the interaction interface with IFT22 (Appendix Fig S7).…”