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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

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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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Growth plate defects in a patient with mutations in IFT81.(A) X-ray of formalin fixed distal femur at 19 months of age showing irregular metaphyseal margin (arrow). (B,C) Picrosirius Red-Haematoxylin staining of same distal femur (B) magnified in (C) showing irregular hypertrophic column formation and lack of normal progressive enlargement of hypertrophic chondrocytes. Arrow points to an irregular collagenous band transecting the growth plate. (D,E) Differences between control and IFT81 defective growth plates. (D) Control. (E) R98-443. Bone is represented in red and cartilage in blue.
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f4: Growth plate defects in a patient with mutations in IFT81.(A) X-ray of formalin fixed distal femur at 19 months of age showing irregular metaphyseal margin (arrow). (B,C) Picrosirius Red-Haematoxylin staining of same distal femur (B) magnified in (C) showing irregular hypertrophic column formation and lack of normal progressive enlargement of hypertrophic chondrocytes. Arrow points to an irregular collagenous band transecting the growth plate. (D,E) Differences between control and IFT81 defective growth plates. (D) Control. (E) R98-443. Bone is represented in red and cartilage in blue.

Mentions: While the data presented here demonstrate that IFT81 is required for normal cilia architecture and Hh signaling, how mutations in this gene affect skeletal morphogenesis remains unclear. Since most of the skeletal ciliopathies affect Hh signaling, and differentiation of growth plate chondrocytes is regulated in part by Indian Hedgehog (IHH), it is likely that altered IHH signaling due to defective cilia influences bone morphogenesis in SRPS52549505152. To determine the involvement of mutations in IFT81 in this process, histologic analyses were performed using distal femur growth plates from case R98-443A (Fig. 4). Sections of growth plate were stained with picrosirius red and showed disorganization of chondrocytes in the proliferative zone, with short columns of cells dispersed in more than one plane (Fig. 4). There was a very short hypertrophic zone with poor column formation and lack of the normal progressive increasing size of hypertrophic chondrocytes as they approach the primary spongiosum (Fig. 4B,C). Interestingly, an unusual band of collagenous extracellular matrix with rounded cells was ectopically positioned in the middle of the proliferative zone and the staining was suggestive of a bone-like matrix (arrow in Fig. 4C).


Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome
Growth plate defects in a patient with mutations in IFT81.(A) X-ray of formalin fixed distal femur at 19 months of age showing irregular metaphyseal margin (arrow). (B,C) Picrosirius Red-Haematoxylin staining of same distal femur (B) magnified in (C) showing irregular hypertrophic column formation and lack of normal progressive enlargement of hypertrophic chondrocytes. Arrow points to an irregular collagenous band transecting the growth plate. (D,E) Differences between control and IFT81 defective growth plates. (D) Control. (E) R98-443. Bone is represented in red and cartilage in blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Growth plate defects in a patient with mutations in IFT81.(A) X-ray of formalin fixed distal femur at 19 months of age showing irregular metaphyseal margin (arrow). (B,C) Picrosirius Red-Haematoxylin staining of same distal femur (B) magnified in (C) showing irregular hypertrophic column formation and lack of normal progressive enlargement of hypertrophic chondrocytes. Arrow points to an irregular collagenous band transecting the growth plate. (D,E) Differences between control and IFT81 defective growth plates. (D) Control. (E) R98-443. Bone is represented in red and cartilage in blue.
Mentions: While the data presented here demonstrate that IFT81 is required for normal cilia architecture and Hh signaling, how mutations in this gene affect skeletal morphogenesis remains unclear. Since most of the skeletal ciliopathies affect Hh signaling, and differentiation of growth plate chondrocytes is regulated in part by Indian Hedgehog (IHH), it is likely that altered IHH signaling due to defective cilia influences bone morphogenesis in SRPS52549505152. To determine the involvement of mutations in IFT81 in this process, histologic analyses were performed using distal femur growth plates from case R98-443A (Fig. 4). Sections of growth plate were stained with picrosirius red and showed disorganization of chondrocytes in the proliferative zone, with short columns of cells dispersed in more than one plane (Fig. 4). There was a very short hypertrophic zone with poor column formation and lack of the normal progressive increasing size of hypertrophic chondrocytes as they approach the primary spongiosum (Fig. 4B,C). Interestingly, an unusual band of collagenous extracellular matrix with rounded cells was ectopically positioned in the middle of the proliferative zone and the staining was suggestive of a bone-like matrix (arrow in Fig. 4C).

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