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Miriam Schmidts - One of the best experts on this subject based on the ideXlab platform.
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correction corrigendum tctex1d2 mutations underlie jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature Communications, 2016Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:Nature Communications 6: Article number:7074 (2015); Published: 05 June 2015; Updated: 29 Marrch 2016 The financial support for this article was not fully acknowledged. The Acknowledgements should have included the following: PLB was supported by the National Institute for Health Research BiomedicalResearch Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
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TCTEX1D2 mutations underlie Jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature communications, 2015Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating Thoracic Dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
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Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease.
Human Mutation, 2013Co-Authors: Miriam Schmidts, Dinu Antony, Valeska Frank, Tobias Eisenberger, Saeed Al Turki, Albane A Bizet, Suzanne Rix, Christian Decker, Nadine Bachmann, Martin BaldAbstract:Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating Thoracic Dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal Dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal Dystrophy.
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exome sequencing identifies dync2h1 mutations as a common cause of asphyxiating Thoracic Dystrophy jeune syndrome without major polydactyly renal or retinal involvement
Journal of Medical Genetics, 2013Co-Authors: Miriam Schmidts, Dinu Antony, Heleen H Arts, Richard David Emes, Ernie M H F Bongers, Zhimin Yap, Machteld M Oud, Lonneke Duijkers, Jim Stalker, Janbart L YntemaAbstract:Background Jeune asphyxiating Thoracic Dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1 . Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. Aims and methods To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. Results and conclusions We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the Thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.
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Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating Thoracic Dystrophy
2013Co-Authors: Miriam Schmidts, Heleen H Arts, Andreas Zankl, Richard David Emes, Jeune Asphyxiating, Thoracic Dystrophy, Julia Vodopiutz, Sonia Christou-savina, Claudio R. CortésAbstract:Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 ia m ifi io c n n ry932 The American Journal of Human Genetics 93, 932–944, Novemnonmotile monocilia on the surface of most cells of mam-mals, birds, amphibians, and fish, are implicated in divers
Sylvia E. C. Van Beersum - One of the best experts on this subject based on the ideXlab platform.
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correction corrigendum tctex1d2 mutations underlie jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature Communications, 2016Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:Nature Communications 6: Article number:7074 (2015); Published: 05 June 2015; Updated: 29 Marrch 2016 The financial support for this article was not fully acknowledged. The Acknowledgements should have included the following: PLB was supported by the National Institute for Health Research BiomedicalResearch Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
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TCTEX1D2 mutations underlie Jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature communications, 2015Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating Thoracic Dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Yuqing Hou - One of the best experts on this subject based on the ideXlab platform.
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correction corrigendum tctex1d2 mutations underlie jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature Communications, 2016Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:Nature Communications 6: Article number:7074 (2015); Published: 05 June 2015; Updated: 29 Marrch 2016 The financial support for this article was not fully acknowledged. The Acknowledgements should have included the following: PLB was supported by the National Institute for Health Research BiomedicalResearch Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
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TCTEX1D2 mutations underlie Jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature communications, 2015Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating Thoracic Dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Dorus A. Mans - One of the best experts on this subject based on the ideXlab platform.
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correction corrigendum tctex1d2 mutations underlie jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature Communications, 2016Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:Nature Communications 6: Article number:7074 (2015); Published: 05 June 2015; Updated: 29 Marrch 2016 The financial support for this article was not fully acknowledged. The Acknowledgements should have included the following: PLB was supported by the National Institute for Health Research BiomedicalResearch Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
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TCTEX1D2 mutations underlie Jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature communications, 2015Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating Thoracic Dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Jean-marc Plaza - One of the best experts on this subject based on the ideXlab platform.
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correction corrigendum tctex1d2 mutations underlie jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature Communications, 2016Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:Nature Communications 6: Article number:7074 (2015); Published: 05 June 2015; Updated: 29 Marrch 2016 The financial support for this article was not fully acknowledged. The Acknowledgements should have included the following: PLB was supported by the National Institute for Health Research BiomedicalResearch Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
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TCTEX1D2 mutations underlie Jeune asphyxiating Thoracic Dystrophy with impaired retrograde intraflagellar transport
Nature communications, 2015Co-Authors: Miriam Schmidts, Yuqing Hou, Claudio Cortes, Dorus A. Mans, Céline Huber, Karsten Boldt, Mitali P. Patel, Jeroen Van Reeuwijk, Jean-marc Plaza, Sylvia E. C. Van BeersumAbstract:The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating Thoracic Dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
