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

View Article: PubMed Central - PubMed

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.

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Mutations in IFT81 cause SRP syndrome.Radiographic findings in R98-443 and R13-147A. (A,F) show dolicocephaly, prominent occiput, and midface hypoplasia. (B,G) show long narrow thoraxes, handlebar clavicles in R98-443 and very short horizontal ribs in R13-147. (C) Upper extremity of R98-443 demonstrating shortened humerus and radius, and short, abnormally shaped ulna. (H) Lower extremity of R13-174 showing marked deficiency of the femur, tibia and fibula. (D,I) show brachydactyly and polydactyly and poor mineralization (arrow) in SRP case R13-174. (E,J) Chromatograms illustrating compound heterozygosity for mutations found in each case.
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f1: Mutations in IFT81 cause SRP syndrome.Radiographic findings in R98-443 and R13-147A. (A,F) show dolicocephaly, prominent occiput, and midface hypoplasia. (B,G) show long narrow thoraxes, handlebar clavicles in R98-443 and very short horizontal ribs in R13-147. (C) Upper extremity of R98-443 demonstrating shortened humerus and radius, and short, abnormally shaped ulna. (H) Lower extremity of R13-174 showing marked deficiency of the femur, tibia and fibula. (D,I) show brachydactyly and polydactyly and poor mineralization (arrow) in SRP case R13-174. (E,J) Chromatograms illustrating compound heterozygosity for mutations found in each case.

Mentions: We ascertained a term male (International Skeletal Dysplasia Registry reference number R98-443) recognized at birth to have features consistent with ATD. The clinical findings are summarized in Table 1. The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput (Fig. 1A), short ribs, handlebar clavicles (Fig. 1B) and short, curved appendicular bones, with the upper limbs particularly abnormally shaped (Fig. 1C). There was no polydactyly on either the hands or feet (Fig. 1D). The infant developed respiratory distress soon after birth and was initially treated by supplemental oxygen. His respiratory compromised worsened over time and he died at 19 months of age.


Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome
Mutations in IFT81 cause SRP syndrome.Radiographic findings in R98-443 and R13-147A. (A,F) show dolicocephaly, prominent occiput, and midface hypoplasia. (B,G) show long narrow thoraxes, handlebar clavicles in R98-443 and very short horizontal ribs in R13-147. (C) Upper extremity of R98-443 demonstrating shortened humerus and radius, and short, abnormally shaped ulna. (H) Lower extremity of R13-174 showing marked deficiency of the femur, tibia and fibula. (D,I) show brachydactyly and polydactyly and poor mineralization (arrow) in SRP case R13-174. (E,J) Chromatograms illustrating compound heterozygosity for mutations found in each case.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035930&req=5

f1: Mutations in IFT81 cause SRP syndrome.Radiographic findings in R98-443 and R13-147A. (A,F) show dolicocephaly, prominent occiput, and midface hypoplasia. (B,G) show long narrow thoraxes, handlebar clavicles in R98-443 and very short horizontal ribs in R13-147. (C) Upper extremity of R98-443 demonstrating shortened humerus and radius, and short, abnormally shaped ulna. (H) Lower extremity of R13-174 showing marked deficiency of the femur, tibia and fibula. (D,I) show brachydactyly and polydactyly and poor mineralization (arrow) in SRP case R13-174. (E,J) Chromatograms illustrating compound heterozygosity for mutations found in each case.
Mentions: We ascertained a term male (International Skeletal Dysplasia Registry reference number R98-443) recognized at birth to have features consistent with ATD. The clinical findings are summarized in Table 1. The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput (Fig. 1A), short ribs, handlebar clavicles (Fig. 1B) and short, curved appendicular bones, with the upper limbs particularly abnormally shaped (Fig. 1C). There was no polydactyly on either the hands or feet (Fig. 1D). The infant developed respiratory distress soon after birth and was initially treated by supplemental oxygen. His respiratory compromised worsened over time and he died at 19 months of age.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus