Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans
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| Title: | Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans |
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| Authors: | Erica E. Davis, Miriam Schmidts, Christine Bole-Feysot, Dan Doherty, Bernard S. Kaplan, Toby W. Hurd, Steven J.M. Jones, Andreas Zankl, Sophie Saunier, Patrick Nitschke, Edgar A. Otto, Friedhelm Hildebrandt, Jane Hartley, Bertrand Knebelmann, Rannar Airik, Eamonn R. Maher, Hülya Kayserili, Peter Trnka, Heon Yung Gee, Anna Lehman, Emilie Filhol, Pauline Krug, Ian D. Krantz, Jagesh V. Shah, Kálmán Tory, Alexandru Constantinescu, Chunmei Li, Shing Hei Zhan, Paul Leo, Markus Schueler, Hannah M. Mitchison, Nicholas Katsanis, Brooke Gardiner, Khemchand N. Moorani, Aideen M. McInerney-Leo, Albane A. Bizet, Peter G. Czarnecki, Peter J. Scambler, Stéphane Burtey, Fiona Haslam McKenzie, Emma L. Duncan, Attila Szabo, Daniela A. Braun, Jonathan D. Porath, Beyhan Tüysüz, Michel R. Leroux, Matthew A. Brown, Philip L. Beales, Jan Halbritter |
| Contributors: | SE/AOK/K/I. Sz. Gyermekgyógyászati Klinika, Semmelweis Egyetem, College of Medicine, Dept. of Pharmacology, Jan Halbritter, Albane A. Bizet, Miriam Schmidts, Jonathan D. Porath, Daniela A. Braun, Heon Yung Gee, Aideen M. McInerney-Leo, Pauline Krug, Emilie Filhol, Erica E. Davis, Rannar Airik, Peter G. Czarnecki, Anna M. Lehman, Peter Trnka, Patrick Nitschke´, Christine Bole-Feysot, Markus Schueler, Bertrand Knebelmann, Ste´phane Burtey, Attila J. Szabo´, Ka´lma´n Tory, Paul J. Leo, Brooke Gardiner, Fiona A. McKenzie, Andreas Zankl, Matthew A. Brown, Jane L. Hartley, Eamonn R. Maher, Chunmei Li, Michel R. Leroux, Peter J. Scambler, Shing H. Zhan, Steven J. Jones, Hu¨lya Kayserili, Beyhan Tuysuz, Khemchand N. Moorani, Alexandru Constantinescu, Ian D. Krantz, Bernard S. Kaplan, Jagesh V. Shah, UK10K Consortium, Toby W. Hurd, Dan Doherty, Nicholas Katsanis, Emma L. Duncan, Edgar A. Otto, Philip L. Beales, Hannah M. Mitchison, Sophie Saunier, Friedhelm Hildebrandt, Gee, Heon Yung |
| Source: | Halbritter, J, Bizet, A A, Schmidts, M, Porath, J D, Braun, D A, Gee, H Y, McInerney-Leo, A M, Krug, P, Filhol, E, Davis, E E, Airik, R, Czarnecki, P G, Lehman, A M, Trnka, P, Nitschké, P, Bole-Feysot, C, Schueler, M, Knebelmann, B, Burtey, S, Szabó, A J, Tory, K, Leo, P J, Gardiner, B, McKenzie, F A, Zankl, A, Brown, M A, Hartley, J L, Maher, E R, Li, C, Leroux, M R, Scambler, P J, Zhan, S H, Jones, S J, Kayserili, H, Tuysuz, B, Moorani, K N, Constantinescu, A, Krantz, I D, Kaplan, B S, Shah, J V, Hurd, T W, Doherty, D, Katsanis, N, Duncan, E L, Otto, E A, Beales, P L, Mitchison, H M & Saunier, S & Hildebrandt, F 2013, ' Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans ', American Journal of Human Genetics, vol. 93, no. 5, pp. 915-25 . https://doi.org/10.1016/j.ajhg.2013.09.012 American Journal of Human Genetics |
| Publisher Information: | Elsevier BV, 2013. |
| Publication Year: | 2013 |
| Subject Terms: | Cytoplasmic Dyneins, Male, 0301 basic medicine, Rib-Polydactyly Syndrome, frameshift mutation, Retinitis Pigmentosa/pathology, mucociliary transport, Intraflagellar Transport Protein, Cerebellar Ataxia/genetics, Dyneins/genetics, jeune syndrome, Ectodermal Dysplasia, Genetics(clinical), exon, gene mutation, European Continental Ancestry Group/genetics, genetic conservation, Bone and Bones/pathology, Zebrafish, cellular distribution, 2. Zero hunger, 0303 health sciences, allele, article, Intracellular Signaling Peptides and Proteins, Cerebellar Ataxia/pathology, Kidney Diseases, Cystic, Ectodermal Dysplasia/genetics, 3. Good health, Cytoplasmic Dyneins/genetics, Van-Creveld-Syndrome, molecular motor, Intracellular Signaling Peptides and Proteins/metabolism, Phenotype, aplasia, Ellis-Van Creveld Syndrome/genetics, Gene Knockdown Techniques, Cystic/genetics, Kidney Diseases, Female, Retinitis Pigmentosa, Ellis-Van Creveld Syndrome/pathology, Asian Continental Ancestry Group, 2716 Genetics (clinical), intron, Cerebellar Ataxia, phenotype, Ellis-Van Creveld Syndrome, Retinitis Pigmentosa/genetics, European Continental Ancestry Group, Molecular Sequence Data, Asphyxiating Thoracic Dystrophy, Bone and Bones/metabolism, Bone and Bones, Zebrafish/genetics, Cystic, Craniosynostoses, 03 medical and health sciences, 1311 Genetics, Genetic, Asian People, Joubert syndrome, Cytoplasmic Dyneins/metabolism, Genetics, Animals, Humans, Asian Continental Ancestry Group/genetics, eukaryotic flagellum, human, Amino Acid Sequence, Alleles, Craniosynostoses/genetics, hypoplasia, Danio rerio, nonhuman, gene interaction, missense mutation, Dyneins, Epistasis, Genetic, excision repair, Fibroblasts, Fibroblasts/pathology, intraflagellar transport B, Bone and Bones/abnormalities, Ectodermal Dysplasia/pathology, Cystic/pathology, Mutation, nephronophthisis, Epistasis, Dyneins/metabolism, Craniosynostoses/pathology, Intracellular Signaling Peptides and Proteins/genetics |
| Description: | Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A. |
| Document Type: | Article Conference object Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2013.09.012 |
| Access URL: | http://www.cell.com/article/S0002929713004527/pdf https://pubmed.ncbi.nlm.nih.gov/24140113 https://www.research.ed.ac.uk/portal/files/11294950/Defects_in_the_IFT_B_Component_IFT172_Cause_Jeune_and_Mainzer_Saldino_Syndromes_in_Humans.pdf https://espace.library.uq.edu.au/view/UQ:319462 https://www.cell.com/article/S0002929713004527/abstract https://www.sciencedirect.com/science/article/pii/S0002929713004527 https://doi.org/10.1016/j.ajhg.2013.09.012 https://www.pure.ed.ac.uk/ws/files/11294950/Defects_in_the_IFT_B_Component_IFT172_Cause_Jeune_and_Mainzer_Saldino_Syndromes_in_Humans.pdf https://hdl.handle.net/20.500.11820/0ef852bf-ca67-4025-8707-787abc2ed2c4 https://discovery-pp.ucl.ac.uk/id/eprint/1418407/ |
| Rights: | CC BY CC BY NC ND |
| Accession Number: | edsair.doi.dedup.....f8616341e9eb8d02c62bb1e3dbb2d4dc |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A. |
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| ISSN: | 00029297 |
| DOI: | 10.1016/j.ajhg.2013.09.012 |