Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia
| Autor: | Ivan Duran, Daniel H. Cohn, Michael J. Bamshad, Ralph S. Lachman, Deborah A. Nickerson, Faisal Qureshi, S. Paige Taylor, Suzanne M. Jacques, Robert Wallerstein, Wenjuan Zhang, Deborah Krakow, Jorge H. Martin |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Retrograde transport IFT 030105 genetics & heredity Biology Short rib polydactyly syndrome Ciliopathies 03 medical and health sciences SRPS Intraflagellar transport Locus heterogeneity Ciliogenesis medicine Cilia lcsh:QH573-671 Endochondral ossification Genetics Short rib – polydactyly syndrome Polydactyly lcsh:Cytology Cilium Research IFT121 Cell Biology medicine.disease Skeletal ciliopathy 030104 developmental biology Cartilage IFT-A complex IFT43 |
| Zdroj: | Cilia Cilia, Vol 6, Iss 1, Pp 1-13 (2017) |
| ISSN: | 2046-2530 |
| Popis: | Background Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function. Results Herein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43. Conclusions This study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors. Electronic supplementary material The online version of this article (doi:10.1186/s13630-017-0051-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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