共查询到20条相似文献,搜索用时 15 毫秒
1.
Heike Olbrich Miriam Schmidts Claudius Werner Alexandros Onoufriadis Niki T. Loges Johanna Raidt Nora Fanni Banki Amelia Shoemark Tom Burgoyne Saeed Al Turki Matthew E. Hurles Gabriele Köhler Josef Schroeder Gudrun Nürnberg Peter Nürnberg Eddie M.K. Chung Richard Reinhardt Heymut Omran 《American journal of human genetics》2012,91(4):672-684
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Inga M. Höben Rim Hjeij Heike Olbrich Gerard W. Dougherty Tabea Nöthe-Menchen Isabella Aprea Diana Frank Petra Pennekamp Bernd Dworniczak Julia Wallmeier Johanna Raidt Kim G. Nielsen Maria C. Philipsen Francesca Santamaria Laura Venditto Israel Amirav Huda Mussaffi Freerk Prenzel Heymut Omran 《American journal of human genetics》2018,102(5):973-984
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Esther Kott Marie Legendre Bruno Copin Jean-Fran?ois Papon Florence Dastot-Le?Moal Guy Montantin Philippe Duquesnoy William Piterboth Daniel Amram Laurence Bassinet Julie Beucher Nicole Beydon Eric Deneuville Véronique Houdouin Hubert Journel Jocelyne Just Nadia Nathan Aline Tamalet Nathalie Collot Ludovic Jeanson Morgane Le?Gouez Benoit Vallette Anne-Marie Vojtek Ralph Epaud André Coste Annick Clement Bruno Housset Bruno Louis Estelle Escudier Serge Amselem 《American journal of human genetics》2013,93(3):561-570
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Esther Kott Marie Legendre Bruno Copin Jean-François Papon Florence Dastot-Le Moal Guy Montantin Philippe Duquesnoy William Piterboth Daniel Amram Laurence Bassinet Julie Beucher Nicole Beydon Eric Deneuville Véronique Houdouin Hubert Journel Jocelyne Just Nadia Nathan Aline Tamalet Nathalie Collot Ludovic Jeanson Morgane Le Gouez Benoit Vallette Anne-Marie Vojtek Ralph Epaud André Coste Annick Clement Bruno Housset Bruno Louis Estelle Escudier Serge Amselem 《American journal of human genetics》2013
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Michael?R. Knowles Margaret?W. Leigh Lawrence?E. Ostrowski Lu Huang Johnny?L. Carson Milan?J. Hazucha Weining Yin Jonathan?S. Berg Stephanie?D. Davis Sharon?D. Dell Thomas?W. Ferkol Margaret Rosenfeld Scott?D. Sagel Carlos?E. Milla Kenneth?N. Olivier Emily?H. Turner Alexandra?P. Lewis Michael?J. Bamshad Deborah?A. Nickerson Jay Shendure Maimoona?A. Zariwala the Genetic Disorders of Mucociliary Clearance?Consortium 《American journal of human genetics》2013,92(1):99-106
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 14 genes, but they collectively account for only ∼60% of all PCD. To identify mutations that cause PCD, we performed exome sequencing on six unrelated probands with ciliary outer dynein arm (ODA) defects. Mutations in CCDC114, an ortholog of the Chlamydomonas reinhardtii motility gene DCC2, were identified in a family with two affected siblings. Sanger sequencing of 67 additional individuals with PCD with ODA defects from 58 families revealed CCDC114 mutations in 4 individuals in 3 families. All 6 individuals with CCDC114 mutations had characteristic oto-sino-pulmonary disease, but none had situs abnormalities. In the remaining 5 individuals with PCD who underwent exome sequencing, we identified mutations in two genes (DNAI2, DNAH5) known to cause PCD, including an Ashkenazi Jewish founder mutation in DNAI2. These results revealed that mutations in CCDC114 are a cause of ciliary dysmotility and PCD and further demonstrate the utility of exome sequencing to identify genetic causes in heterogeneous recessive disorders. 相似文献
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Heike Olbrich Carolin Cremers Niki?T. Loges Claudius Werner Kim?G. Nielsen June?K. Marthin Maria Philipsen Julia Wallmeier Petra Pennekamp Tabea Menchen Christine Edelbusch Gerard?W. Dougherty Oliver Schwartz Holger Thiele Janine Altmüller Frank Rommelmann Heymut Omran 《American journal of human genetics》2015,97(4):546-554
Multiciliated epithelial cells protect the upper and lower airways from chronic bacterial infections by moving mucus and debris outward. Congenital disorders of ciliary beating, referred to as primary ciliary dyskinesia (PCD), are characterized by deficient mucociliary clearance and severe, recurrent respiratory infections. Numerous genetic defects, most of which can be detected by transmission electron microscopy (TEM), are so far known to cause different abnormalities of the ciliary axoneme. However, some defects are not regularly discernable by TEM because the ciliary architecture of the axoneme remains preserved. This applies in particular to isolated defects of the nexin links, also known as the nexin-dynein regulatory complex (N-DRC), connecting the peripheral outer microtubular doublets. Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect. Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families. 相似文献
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《American journal of human genetics》2013,93(4):711-720
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders. 相似文献
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Victoria H. Castleman Leila Romio Rahul Chodhari Robert A. Hirst Sandra C.P. de Castro Keith A. Parker Patricia Ybot-Gonzalez Richard D. Emes Stephen W. Wilson Colin Wallis Colin A. Johnson Rene J. Herrera Andrew Rutman Mellisa Dixon Amelia Shoemark Andrew Bush Claire Hogg R. Mark Gardiner Orit Reish Nicholas D.E. Greene Christopher O'Callaghan Saul Purton Eddie M.K. Chung Hannah M. Mitchison 《American journal of human genetics》2009,84(2):197-209
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder arising from dysmotility of motile cilia and sperm. This is associated with a variety of ultrastructural defects of the cilia and sperm axoneme that affect movement, leading to clinical consequences on respiratory-tract mucociliary clearance and lung function, fertility, and left-right body-axis determination. We performed whole-genome SNP-based linkage analysis in seven consanguineous families with PCD and central-microtubular-pair abnormalities. This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0). Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head. In situ hybridization of murine Rsph9 shows gene expression restricted to regions containing motile cilia. Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile, “9+2”-structure cilia and flagella. This effect is rescued by reintroduction of gene expression for restoration of a normal beat pattern in zebrafish. Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish. 相似文献
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Niki Tomas Loges Heike Olbrich Anita Becker-Heck Karsten Häffner Angelina Heer Christina Reinhard Miriam Schmidts Andreas Kispert Maimoona A. Zariwala Margaret W. Leigh Michael R. Knowles Hanswalter Zentgraf Horst Seithe Gudrun Nürnberg Peter Nürnberg Richard Reinhardt Heymut Omran 《American journal of human genetics》2009,85(6):883-889
Genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility in primary ciliary dyskinesia (PCD). The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein complexes responsible for cilia-beat generation and regulation, respectively. Here, we demonstrate that large genomic deletions, as well as point mutations involving LRRC50, are responsible for a distinct PCD variant that is characterized by a combined defect involving assembly of the ODAs and IDAs. Functional analyses showed that LRRC50 deficiency disrupts assembly of distally and proximally DNAH5- and DNAI2-containing ODA complexes, as well as DNALI1-containing IDA complexes, resulting in immotile cilia. On the basis of these findings, we assume that LRRC50 plays a role in assembly of distinct dynein-arm complexes. 相似文献
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Tamara Paff Niki T. Loges Isabella Aprea Kaman Wu Zeineb Bakey Eric G. Haarman Johannes M.A. Daniels Erik A. Sistermans Natalija Bogunovic Gerard W. Dougherty Inga M. Höben Jörg Große-Onnebrink Anja Matter Heike Olbrich Claudius Werner Gerard Pals Miriam Schmidts Heymut Omran Dimitra Micha 《American journal of human genetics》2017,100(1):160-168
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《American journal of human genetics》2014,95(3):257-274
A diverse family of cytoskeletal dynein motors powers various cellular transport systems, including axonemal dyneins generating the force for ciliary and flagellar beating essential to movement of extracellular fluids and of cells through fluid. Multisubunit outer dynein arm (ODA) motor complexes, produced and preassembled in the cytosol, are transported to the ciliary or flagellar compartment and anchored into the axonemal microtubular scaffold via the ODA docking complex (ODA-DC) system. In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality. Here, by combined high-throughput mapping and sequencing, we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families whose cilia showed a complete loss of ODAs and severely impaired ciliary beating. Consistent with the laterality defects observed in these individuals, we found Ccdc151 expressed in vertebrate left-right organizers. Homozygous zebrafish ccdc151ts272a and mouse Ccdc151Snbl mutants display a spectrum of situs defects associated with complex heart defects. We demonstrate that CCDC151 encodes an axonemal coiled coil protein, mutations in which abolish assembly of CCDC151 into respiratory cilia and cause a failure in axonemal assembly of the ODA component DNAH5 and the ODA-DC-associated components CCDC114 and ARMC4. CCDC151-deficient zebrafish, planaria, and mice also display ciliary dysmotility accompanied by ODA loss. Furthermore, CCDC151 coimmunoprecipitates CCDC114 and thus appears to be a highly evolutionarily conserved ODA-DC-related protein involved in mediating assembly of both ODAs and their axonemal docking machinery onto ciliary microtubules. 相似文献
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Alexandros Onoufriadis Tamara Paff Dinu Antony Amelia Shoemark Dimitra Micha Bertus Kuyt Miriam Schmidts Stavroula Petridi Jeanette?E. Dankert-Roelse Eric?G. Haarman Johannes?M.A. Daniels Richard?D. Emes Robert Wilson Claire Hogg Peter?J. Scambler Eddie?M.K. Chung UKK Gerard Pals Hannah?M. Mitchison 《American journal of human genetics》2013,92(1):88-98
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Mahmoud R. Fassad Amelia Shoemark Pierrick le Borgne France Koll Mitali Patel Mellisa Dixon Jane Hayward Charlotte Richardson Emily Frost Lucy Jenkins Thomas Cullup Eddie M.K. Chung Michel Lemullois Anne Aubusson-Fleury Claire Hogg David R. Mitchell Anne-Marie Tassin Hannah M. Mitchison 《American journal of human genetics》2018,102(5):956-972
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Philippe Duquesnoy Laetitia Vincensini Judy Freshour André Coste Jacques de Blic Guy Montantin Anne-Marie Vojtek Annick Clément Philippe Bastin Serge Amselem 《American journal of human genetics》2009,85(6):890-4219
Cilia and flagella are evolutionarily conserved structures that play various physiological roles in diverse cell types. Defects in motile cilia result in primary ciliary dyskinesia (PCD), the most prominent ciliopathy, characterized by the association of respiratory symptoms, male infertility, and, in nearly 50% of cases, situs inversus. So far, most identified disease-causing mutations involve genes encoding various ciliary components, such those belonging to the dynein arms that are essential for ciliary motion. Following a candidate-gene approach based on data from a mutant strain of the biflagellated alga Chlamydomonas reinhardtii carrying an ODA7 defect, we identified four families with a PCD phenotype characterized by the absence of both dynein arms and loss-of-function mutations in the human orthologous gene called LRRC50. Functional analyses performed in Chlamydomonas reinhardtii and in another flagellated protist, Trypanosoma brucei, support a key role for LRRC50, a member of the leucine-rich-repeat superfamily, in cytoplasmic preassembly of dynein arms. 相似文献
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Esther Kott Philippe Duquesnoy Bruno Copin Marie Legendre Florence Dastot-Le?Moal Guy Montantin Ludovic Jeanson Aline Tamalet Jean-Fran?ois Papon Jean-Pierre Siffroi Nathalie Rives Valérie Mitchell Jacques de?Blic André Coste Annick Clement Denise Escalier Aminata Touré Estelle Escudier Serge Amselem 《American journal of human genetics》2012,91(5):958-964
Primary ciliary dyskinesia (PCD) is a group of autosomal-recessive disorders resulting from cilia and sperm-flagella defects, which lead to respiratory infections and male infertility. Most implicated genes encode structural proteins that participate in the composition of axonemal components, such as dynein arms (DAs), that are essential for ciliary and flagellar movements; they explain the pathology in fewer than half of the affected individuals. We undertook this study to further understand the pathogenesis of PCD due to the absence of both DAs. We identified, via homozygosity mapping, an early frameshift in LRRC6, a gene that encodes a leucine-rich-repeat (LRR)-containing protein. Subsequent analyses of this gene mainly expressed in testis and respiratory cells identified biallelic mutations in several independent individuals. The situs inversus observed in two of them supports a key role for LRRC6 in embryonic nodal cilia. Study of native LRRC6 in airway epithelial cells revealed that it localizes to the cytoplasm and within cilia, whereas it is absent from cells with loss-of-function mutations, in which DA protein markers are also missing. These results are consistent with the transmission-electron-microscopy data showing the absence of both DAs in cilia or flagella from individuals with LRRC6 mutations. In spite of structural and functional similarities between LRRC6 and DNAAF1, another LRR-containing protein involved in the same PCD phenotype, the two proteins are not redundant. The evolutionarily conserved LRRC6, therefore, emerges as an additional player in DA assembly, a process that is essential for proper axoneme building and that appears to be much more complex than was previously thought. 相似文献
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