316 results on '"Schmidts, M."'
Search Results
2. Skills Training in Medical Education - influence of previous experience on the acceptance and benefit of selected training models at the Karl Landsteiner University of Health Sciences
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Schober, S, Schmidts, M, Schober, S, and Schmidts, M
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- 2024
Catalog
3. Das Multiple Mini Interview im Test - Reliabilitäten eines 6-Stationen Aufnahmeinterviews an der Karl Landsteiner Privatuniversität für Gesundheitswissenschaften
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Schmidts, M, Leidinger, I, Schmidts, M, and Leidinger, I
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- 2024
4. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
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Barkovich, Anthony, Wheway, G, Schmidts, M, Mans, DA, Szymanska, K, Nguyen, TMT, Racher, H, Phelps, IG, Toedt, G, Kennedy, J, and Wunderlich, KA
- Abstract
© 2015 Macmillan Publishers Limited.Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the pri more...
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- 2015
5. Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm.
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Moore, Anthony, Onoufriadis, A, Shoemark, A, Munye, MM, James, CT, Schmidts, M, Patel, M, Rosser, EM, Bacchelli, C, Beales, PL, and Scambler, PJ
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Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and more...
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- 2014
6. Citrin deficiency mimicking mitochondrial depletion syndrome
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Grünert, S. C., Schumann, A., Freisinger, P., Rosenbaum-Fabian, S., Schmidts, M., Mueller, A. J., Beck-Wödl, S., Haack, T. B., Schneider, H., Fuchs, H., Teufel, U., Gramer, G., Hannibal, L., and Spiekerkoetter, U. more...
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- 2020
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7. Elucidating the molecular basis of dynein based ciliopathies
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Brunner, H.G., Schmidts, M., Antony, D., Brunner, H.G., Schmidts, M., and Antony, D.
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Radboud University, 07 februari 2023, Promotor : Brunner, H.G. Co-promotor : Schmidts, M., Contains fulltext : 288653.pdf (Publisher’s version ) (Closed access)
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- 2023
8. IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.
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Bakey, Z., Cabrera, O.A., Hoefele, J., Antony, D., Wu, K.M., Stuck, M.W., Micha, D., Eguether, T., Smith, A.O., Wel, N.N. van der, Wagner, M., Strittmatter, L., Beales, P.L., Jonassen, J.A., Thiffault, I., Cadieux-Dion, M., Boyes, L., Sharif, S., Tüysüz, B., Dunstheimer, D., Niessen, H.W.M., Devine, W., Lo, C.W., Mitchison, H.M., Schmidts, M., Pazour, G.J., Bakey, Z., Cabrera, O.A., Hoefele, J., Antony, D., Wu, K.M., Stuck, M.W., Micha, D., Eguether, T., Smith, A.O., Wel, N.N. van der, Wagner, M., Strittmatter, L., Beales, P.L., Jonassen, J.A., Thiffault, I., Cadieux-Dion, M., Boyes, L., Sharif, S., Tüysüz, B., Dunstheimer, D., Niessen, H.W.M., Devine, W., Lo, C.W., Mitchison, H.M., Schmidts, M., and Pazour, G.J. more...
- Abstract
01 juni 2023, Contains fulltext : 294338.pdf (Publisher’s version ) (Open Access), Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice. more...
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- 2023
9. Outcome Based (Skills?) Curriculum
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Wieser, M, Schmidts, M, Wieser, M, and Schmidts, M
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- 2022
10. Knowledge UND Skills UND Attitudes - das Multiple Mini Interview Aufnahmeverfahren an der Karl Landsteiner Privatuniversität für Gesundheitswissenschaften
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Schmidts, M, Fendt, I, Schmidts, M, and Fendt, I
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- 2022
11. Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases
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Antony, D., Yilmaz, E., Gezdirici, A., Slagter, L., Bakey, Z., Bornaun, H., Tanidir, I.C., Dinh, T., Brunner, H.G., Walentek, P., Arnold, S.J., Backofen, R., Schmidts, M., Antony, D., Yilmaz, E., Gezdirici, A., Slagter, L., Bakey, Z., Bornaun, H., Tanidir, I.C., Dinh, T., Brunner, H.G., Walentek, P., Arnold, S.J., Backofen, R., and Schmidts, M. more...
- Abstract
Contains fulltext : 252030.pdf (Publisher’s version ) (Open Access), Laterality defects are defined by the perturbed left-right arrangement of organs in the body, occurring in a syndromal or isolated fashion. In humans, primary ciliary dyskinesia (PCD) is a frequent underlying condition of defective left-right patterning, where ciliary motility defects also result in reduced airway clearance, frequent respiratory infections, and infertility. Non-motile cilia dysfunction and dysfunction of non-ciliary genes can also result in disturbances of the left-right body axis. Despite long-lasting genetic research, identification of gene mutations responsible for left-right patterning has remained surprisingly low. Here, we used whole-exome sequencing with Copy Number Variation (CNV) analysis to delineate the underlying molecular cause in 35 mainly consanguineous families with laterality defects. We identified causative gene variants in 14 families with a majority of mutations detected in genes previously associated with PCD, including two small homozygous CNVs. None of the patients were previously clinically diagnosed with PCD, underlining the importance of genetic diagnostics for PCD diagnosis and adequate clinical management. Identified variants in non-PCD-associated genes included variants in PKD1L1 and PIFO, suggesting that dysfunction of these genes results in laterality defects in humans. Furthermore, we detected candidate variants in GJA1 and ACVR2B possibly associated with situs inversus. The low mutation detection rate of this study, in line with other previously published studies, points toward the possibility of non-coding genetic variants, putative genetic mosaicism, epigenetic, or environmental effects promoting laterality defects. more...
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- 2022
12. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination
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Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., Zorzi, R. de, Payne, K., Henderson, L.B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J.A., Provitera, V., Schuelke, M., Vandrovcova, J., Groppa, S., Karashova, B.M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J.S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M.D., Maagdenberg, A.M.J.M. van den, Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A.M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B.M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E.Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N.N., Atawneh, O., Lim, S.Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y.A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E.G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., Lonlay, P. de, Cantagrel, V., Aguennouz, M., Khorassani, M. el, Schmidts, M., Alkuraya, F.S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., SYNAPS Study Grp, Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., De Zorzi, R., Payne, K., Henderson, L. B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J. A., Provitera, V., Schuelke, M., Vandrovcova, J., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E. G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., De Lonlay, P., Cantagrel, V., Aguennouz, M., El Khorassani, M., Schmidts, M., Alkuraya, F. S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Van Den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratory of Molecular Biophysics, Department of Biochemistry, Department of Biochemistry, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Department of Medical and Molecular Genetics, King‘s College London, Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Fondazione, Leiden University Medical Center (LUMC), Department of Physiology and Cellular Biophysics [New York, NY, USA], Columbia University College of Physicians and Surgeons, Department of Microbiology, Università degli studi di Catania [Catania], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ceinge, centro di Ingegneria Genetica e Biotecnologie Avanzate, Unité des troubles du sommeil, Centre de référence national sur les maladies rares (narcolepsie, hypersomnie idiopathique, syndrome de Kleine-Levin)-Hôpital Gui-de-Chauliac, Muscular and Neurodegenerative Disease Unit, University of Genoa (UNIGE), Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Indiana University, Indiana University [Bloomington], Indiana University System-Indiana University System, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service métabolisme, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Efthymiou S., Salpietro V., Malintan N., Poncelet M., Kriouile Y., Fortuna S., De Zorzi R., Payne K., Henderson L.B., Cortese A., Maddirevula S., Alhashmi N., Wiethoff S., Ryten M., Botia J.A., Provitera V., Schuelke M., Vandrovcova J., Walsh L., Torti E., Iodice V., Najafi M., Karimiani E.G., Maroofian R., Siquier-Pernet K., Boddaert N., De Lonlay P., Cantagrel V., Aguennouz M., El Khorassani M., Schmidts M., Alkuraya F.S., Edvardson S., Nolano M., Devaux J., Houlden H., Groppa S., Karashova B.M., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., Van Den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Kullmann D., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Zollo M., Heimer G., Dauvilliers Y.A., Minetti C., Al-Khawaja I., Al-Mutairi F., Hamed S., Pipis M., Bettencourt C., Rinaldi S., Efthymiou, Stephanie, Salpietro, Vincenzo, Malintan, Nancy, Poncelet, Mallory, Kriouile, Yamna, Fortuna, Sara, De Zorzi, Rita, Payne, Katelyn, Henderson, Lindsay B, Cortese, Andrea, Maddirevula, Sateesh, Alhashmi, Nadia, Wiethoff, Sarah, Ryten, Mina, Botia, Juan A, Provitera, Vincenzo, Schuelke, Marku, Vandrovcova, Jana, Walsh, Laurence, Torti, Erin, Iodice, Valeria, Najafi, Maryam, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Siquier-Pernet, Karine, Boddaert, Nathalie, De Lonlay, Pascale, Cantagrel, Vincent, Aguennouz, Mhammed, El Khorassani, Mohamed, Schmidts, Miriam, Alkuraya, Fowzan S, Edvardson, Simon, Nolano, Maria, Devaux, Jérôme, Houlden, Henry, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11) more...
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Male ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Nerve Fibers, Myelinated ,Gene Frequency ,Neurodevelopmental Disorder ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Nerve Growth Factor ,Protein Isoforms ,Child ,ComputingMilieux_MISCELLANEOUS ,Myelin Sheath ,neurofascin ,neurodevelopment ,peripheral demyelination ,Allele ,Demyelinating Disease ,Genomics ,neurodevelopment, neurofascin, peripheral demyelination ,Settore MED/39 - Neuropsichiatria Infantile ,Pedigree ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,Child, Preschool ,Peripheral Nerve ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,Neuroglia ,Human ,Adult ,Adolescent ,Nervous System Malformations ,Guillain-Barre Syndrome ,Axon ,Nervous System Malformation ,Ranvier's Nodes ,Humans ,Nerve Growth Factors ,Peripheral Nerves ,Alleles ,Autoantibodies ,Infant ,Protein Isoform ,Original Articles ,Axons ,nervous system ,Neurodevelopmental Disorders ,Cell Adhesion Molecule ,Mutation ,Cell Adhesion Molecules ,Demyelinating Diseases - Abstract
See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres., Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function. more...
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- 2019
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13. Ciliary Dyneins and Dynein Related Ciliopathies
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Antony, D., Brunner, H.G., Schmidts, M., Antony, D., Brunner, H.G., and Schmidts, M.
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Contains fulltext : 237821.pdf (Publisher’s version ) (Open Access), Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field. more...
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- 2021
14. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
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Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Palvadeau, Robin, Sanderson, L.E.; Lanko, K.; Alsagob, M.; Almass, R.; Al-Ahmadi, N.; Najafi, M.; Al-Muhaizea, M.A.; Alzaidan, H.; AlDhalaan, H.; Perenthaler, E.; van der Linde, H.C.; Nikoncuk, A.; Kühn, N. A.; Antony, D.; Owaidah, T.M.; Raskin, S.; Vieira, L. G. D. R.; Mombach, R.; Ahangari, N.; Silveira, T. R. D.; Ameziane, N.; Rolfs, A.; Alharbi, A.; Sabbagh, R. M.; AlAhmadi, K.; Alawam, B.; Ghebeh, H.; AlHargan, A.; Albader, A. A.; Binhumaid, F. S.; Goljan, E.; Monies, D.; Mustafa, O. M.; Aldosary, M.; AlBakheet, A.; Alyounes, B.; Almutairi, F.; Al-Odaib, A;, Aksoy, D. B.; Trabzuni, D.; Rosenfeld, J. A.; Karimiani, E. G.; Meyer, B. F.; Karakaş, B.; Al-Mohanna, F.; Arold, S. T.; Çolak, D.; Maroofian, R.; Houlden, H.; Bertoli-Avella, A. M.; Schmidts, M.; Barakat, T. S.; van Ham, T. J.; Kaya, N., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512); Palvadeau, Robin, Sanderson, L.E.; Lanko, K.; Alsagob, M.; Almass, R.; Al-Ahmadi, N.; Najafi, M.; Al-Muhaizea, M.A.; Alzaidan, H.; AlDhalaan, H.; Perenthaler, E.; van der Linde, H.C.; Nikoncuk, A.; Kühn, N. A.; Antony, D.; Owaidah, T.M.; Raskin, S.; Vieira, L. G. D. R.; Mombach, R.; Ahangari, N.; Silveira, T. R. D.; Ameziane, N.; Rolfs, A.; Alharbi, A.; Sabbagh, R. M.; AlAhmadi, K.; Alawam, B.; Ghebeh, H.; AlHargan, A.; Albader, A. A.; Binhumaid, F. S.; Goljan, E.; Monies, D.; Mustafa, O. M.; Aldosary, M.; AlBakheet, A.; Alyounes, B.; Almutairi, F.; Al-Odaib, A;, Aksoy, D. B.; Trabzuni, D.; Rosenfeld, J. A.; Karimiani, E. G.; Meyer, B. F.; Karakaş, B.; Al-Mohanna, F.; Arold, S. T.; Çolak, D.; Maroofian, R.; Houlden, H.; Bertoli-Avella, A. M.; Schmidts, M.; Barakat, T. S.; van Ham, T. J.; Kaya, N., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine more...
- Abstract
Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function., King Salman Center for Disability Research; NSTIP/King Abdulaziz City for Science and Technology; King Abdullah University of Science and Technology, Office of Sponsored Research; NSTIP/KACST; Netherlands Organisation for Scientific Research (ZonMW Veni); European Union (EU); Horizon 2020; LEaDing Fellowship; Marie Sklodowska-Curie Grant Agreement; Deutsche Forschungsgemeinschaft; European Union (EU); Horizon 2020; European Research Council (ERC); ERC StG TREATCilia; NTSIP/King Abdulaziz City for Science and Technology; King Faisal Specialist Hospital and Research Centre; KFSHRC Research Grant; Brain & Behavior Research Foundation NARSAD Young Investigator Grant; Erasmus MC Fellowship 2017; Erasmus MC Human Disease Model Award 2018; Erasmus University Rotterdam (EUR) Fellowship; Suna and İnan Kıraç Foundation; Koç University Research Center for Translational Medicine (KUTTAM) more...
- Published
- 2021
15. Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
- Author
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Chatron, N, Becker, F, Morsy, H, Schmidts, M, Hardies, K, Tuysuz, B, Roselli, S, Najafi, M, Alkaya, DU, Ashrafzadeh, F, Nabil, A, Omar, T, Maroofian, R, Karimiani, EG, Hussien, H, Kok, F, Ramos, L, Gunes, N, Bilguvar, K, Labalme, A, Alix, E, Sanlaville, D, de Bellescize, J, Poulat, A-L, EuroEpinomics-RES consortium AR working group, Moslemi, A-R, Lerche, H, May, P, Lesca, G, Weckhuysen, S, Tajsharghi, H, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and University of Luxembourg: High Performance Computing - ULHPC [research center] more...
- Subjects
cleft palate ,Epilepsy ,Hypsarrhythmia ,omphalocele ,GAD1 ,Suppression-burs ,Developmental Syndrome ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] ,arthrogryposis - Abstract
Developmental and Epileptic Encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathies caused by bi-allelic loss of function variants in GAD1, as presented by eleven patients from 6 independent consanguineous families. Seizure onset occurred in the two first months of life in all patients. All 10 patients from whom early disease history was available, presented seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early electroencephalography showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before four years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyzes the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele. more...
- Published
- 2020
16. Flow stimulates drug transport in a human kidney proximal tubule-on-a-chip independent of primary cilia
- Author
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Vriend, J., Peters, J.G.P., Nieskens, T.T.G., Skovronova, Renata, Blaimschein, Nina, Schmidts, M., Roepman, R., Schirris, T.J.J., Russel, F.G.M., Masereeuw, R., Wilmer, M.J.G., Vriend, J., Peters, J.G.P., Nieskens, T.T.G., Skovronova, Renata, Blaimschein, Nina, Schmidts, M., Roepman, R., Schirris, T.J.J., Russel, F.G.M., Masereeuw, R., and Wilmer, M.J.G. more...
- Abstract
Contains fulltext : 214147.pdf (publisher's version ) (Open Access)
- Published
- 2020
17. Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
- Author
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Walczak-Sztulpa, Joanna, Posmyk, Renata, Bukowska-Olech, Ewelina M., Wawrocka, Anna, Jamsheer, Aleksander, Oud, M.M., Schmidts, M., Latos-Bielenska, Anna, Wasilewska, Anna, Walczak-Sztulpa, Joanna, Posmyk, Renata, Bukowska-Olech, Ewelina M., Wawrocka, Anna, Jamsheer, Aleksander, Oud, M.M., Schmidts, M., Latos-Bielenska, Anna, and Wasilewska, Anna more...
- Abstract
Contains fulltext : 216634.pdf (publisher's version ) (Open Access)
- Published
- 2020
18. Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
- Author
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Chatron, Nicolas, Becker, Felicitas, Morsy, Heba, Schmidts, M., Hardies, Katia, Tuysuz, Beyhan, Najafi, Maryam, Weckhuysen, Sarah, Tajsharghi, Homa, Chatron, Nicolas, Becker, Felicitas, Morsy, Heba, Schmidts, M., Hardies, Katia, Tuysuz, Beyhan, Najafi, Maryam, Weckhuysen, Sarah, and Tajsharghi, Homa more...
- Abstract
Contains fulltext : 220364.pdf (Publisher’s version ) (Open Access)
- Published
- 2020
19. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume
- Author
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Haworth, S, Shapland, CY, Hayward, C, Prins, BP, Felix, JF, Medina-Gomez, C, Rivadeneira, F, Wang, C, Ahluwalia, TS, Vrijheid, M, Guxens, M, Sunyer, J, Tachmazidou, I, Walter, K, Iotchkova, V, Jackson, A, Cleal, L, Huffmann, J, Min, JL, Sass, L, Timmers, PRHJ, Al Turki, S, Anderson, CA, Anney, R, Antony, D, Artigas, MS, Ayub, M, Bala, S, Barrett, JC, Barroso, I, Beales, P, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, DA, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Danecek, P, Day, INM, Day-Williams, A, Dominiczak, A, Down, T, Du, Y, Dunham, I, Durbin, R, Edkins, S, Ekong, R, Ellis, P, Evans, DM, Farooqi, IS, Fitzpatrick, DR, Flicek, P, Floyd, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Gaunt, TR, Geihs, M, Geschwind, D, Greenwood, CMT, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, AE, Holmans, P, Howie, B, Huang, J, Huang, L, Hubbard, T, Humphries, SE, Hurles, ME, Hysi, P, Jackson, DK, Jamshidi, Y, Joyce, C, Karczewski, KJ, Kaye, J, Keane, T, Kemp, JP, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, van Kogelenberg, M, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, D, Lee, I, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M, MacArthur, DG, Mangino, M, Marchini, J, Marenne, G, Maslen, J, Mathieson, I, McCarthy, S, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Memari, Y, Metrustry, S, Migone, N, Mitchison, HM, Moayyeri, A, Morris, A, Morris, J, Muddyman, D, Muntoni, F, Northstone, K, O'Donovan, MC, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Payne, SJ, Perry, JRB, Pietilainen, O, Plagnol, V, Pollitt, RC, Porteous, DJ, Povey, S, Quail, MA, Quaye, L, Raymond, FL, Rehnstrom, K, Richards, JB, Ridout, CK, Ring, S, Ritchie, GRS, Roberts, N, Robinson, RL, Savage, DB, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, RH, Semple, RK, Serra, E, Sharp, SI, Shaw, A, Shihab, HA, Shin, S-Y, Skuse, D, Small, KS, Smee, C, Smith, BH, Soranzo, N, Southam, L, Spasic-Boskovic, O, Spector, TD, St Clair, D, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Taylor, R, Tian, J, Tobin, MD, Valdes, AM, Vandersteen, AM, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whyte, T, Williams, HJ, Williamson, KA, Wilson, C, Wilson, SG, Wong, K, Xu, C, Yang, J, Zhang, F, Zhang, P, Zheng, H-F, Smith, GD, Fisher, SE, Wilson, JF, Cole, TJ, Fernandez-Orth, D, Bonnelykke, K, Bisgaard, H, Pennell, CE, Jaddoe, VWV, Dedoussis, G, Timpson, N, Zeggini, E, Vitart, V, St Pourcain, B, UK10K Consortium, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, and Child and Adolescent Psychiatry / Psychology more...
- Abstract
Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development. more...
- Published
- 2019
20. Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis
- Author
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Najafi, Maryam, Kordi-Tamandani, Dor Mohammad, Behjati, Farkhondeh, Sadeghi-Bojd, Simin, Bakey, Z., Karimiani, Ehsan Ghayoor, Azarfar, Anoush, and Schmidts, M.
- Subjects
All institutes and research themes of the Radboud University Medical Center ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] - Abstract
Contains fulltext : 202088.pdf (Publisher’s version ) (Open Access)
- Published
- 2019
21. A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East
- Author
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Najafi, Maryam, Tamandani, Dor Mohammad Kordi, Azarfar, Anoush, Bakey, Z., Behjati, Farkhondeh, Antony, D., Karimiani, Ehsan Ghayoor, Schmidts, M., Najafi, Maryam, Tamandani, Dor Mohammad Kordi, Azarfar, Anoush, Bakey, Z., Behjati, Farkhondeh, Antony, D., Karimiani, Ehsan Ghayoor, and Schmidts, M. more...
- Abstract
Contains fulltext : 202449.pdf (publisher's version ) (Open Access)
- Published
- 2019
22. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)
- Author
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Rad, Abolfazl, Altunoglu, Umut, Miller, Rebecca, Maroofian, Reza, James, Kiely N., Caglayan, Ahmet Okay, Wu, K.M., Bakey, Z., Kayserili, H., Schmidts, M., Rad, Abolfazl, Altunoglu, Umut, Miller, Rebecca, Maroofian, Reza, James, Kiely N., Caglayan, Ahmet Okay, Wu, K.M., Bakey, Z., Kayserili, H., and Schmidts, M. more...
- Abstract
Contains fulltext : 204020.pdf (publisher's version ) (Open Access)
- Published
- 2019
23. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume
- Author
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Haworth, S., Shapland, C.Y., Hayward, C. (Caroline), Prins, B.P. (Bram), Felix, J.F. (Janine), Medina-Gomez, M.C. (Carolina), Rivadeneira Ramirez, F. (Fernando), Wang, C., Ahluwalia, TS, Vrijheid, M. (Martine), Guxens Junyent, M. (Mònica), Sunyer, J. (Jordi), Tachmazidou, I, Walter, K., Iotchkova, V, Jackson, A.U. (Anne), Cleal, L., Huffmann, J., Min, J. (Josine), Sass, L., Timmers, P, Al Turki, S., Anderson, CA, Anney, R. (Richard), Antony, D, Soler Artigas, M. (Maria), Ayub, M, Bala, S, Barrett, JC, Barroso, I.E. (Inês), Beales, P., Bentham, J, Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G. (Gerome), Calissano, M, Carss, K, Charlton, R, Chatterjee, K. (Krishna), Chen, L. (Leslie), Ciampi, A. (Antonio), Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, D.A. (David), Cosgrove, C, Cox, T. (Tessa), Craddock, N.J. (Nick), Crooks, L, Curran, S, Curtis, D. (David), Daly, A, Danecek, P, Day, I.N.M. (Ian), Day-Williams, A, Dominiczak, A. (Anna), Down, T, Li, Y. (Yingrui), Dunham, D.M. (David), Durbin, R, Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Paul), Evans, D.M. (David), Farooqi, I.S. (Sadaf), Fitzpatrick, D.R. (David), Flicek, P, Floyd, J. (Jamie), Foley, AR, Franklin, C.S. (Christopher), Futema, M, Gallagher, L. (Louise), Gaunt, T.R. (Tom), Geihs, M, Geschwind, D., Greenwood, J.P. (John), Griffin, H, Grozeva, D. (Detelina), Guo, X.S., Guo, X. (Xiuqing), Gurling, H. (Hugh), Hart, D.J. (Deborah), Hendricks, AE, Holmans, P.A. (Peter), Howie, B, Huang, J. (Jian), Huang, L.R., Hubbard, T., Humphries, S.E. (Steve), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Jackson, DK, Jamshidi, Y. (Yalda), Joyce, C, Karczewski, KJ, Kaye, J. (Jane), Keane, T, Kemp, J.P., Kennedy, K. (Karen), Kent, A. (Alistair), Keogh, J, Khawaja, F, van Kogelenberg, M., Kolb-Kokocinski, A, Lachance, G, Langford, C. (Cordelia), Lawson, D, Lee, I. van der, Lek, M, Li, R. (Rui), Li, Y.R. (Yun), Liang, J.Q., Lin, H., Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M., MacArthur, DG, Mangino, M. (Massimo), Marchini, J. (Jonathan), Marenne, G., Maslen, J., Mathieson, I. (Iain), McCarthy, S. (Sean), Mcguffin, P. (Peter), Mcintosh, A.M. (Andrew), McKechanie, AG, McQuillin, A. (Andrew), Memari, Y, Metrustry, S. (Sarah), Migone, N, Mitchison, H.M. (Hannah), Moayyeri, A. (Alireza), Morris, A.D. (Andrew), Morris, J, Muddyman, D, Muntoni, F., Northstone, K. (Kate), O'Donovan, M. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A, Oualkacha, K., Owen, M.J., Palotie, A. (Aarno), Panoutsopoulou, K, Parker, V., Parr, D., Paternoster, L. (Lavinia), Paunio, T, Payne, F. (Felicity), Payne, SJ, Perry, J.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V, Pollitt, RC, Porteous, D.J. (David J.), Povey, S. (Sue), Quail, MA, Quaye, L. (Lydia), Raymond, FL, Rehnström, K. (Karola), Richards, J.B. (Brent), Ridout, CK, Ring, S.M. (Susan), Ritchie, GRS, Roberts, N. (Nicola), Robinson, RL, Savage, D.B. (David), Scambler, P., Schiffels, S, Schmidts, M, Schoenmakers, N. (Nadia), Scott, RH, Semple, R.K. (Robert), Serra, E, Sharp, S.I., Shaw, A. (Alison), Shihab, HA, Shin, S.-Y., Skuse, D, Small, K.S. (Kerrin), Smee, C, Smith, B.H. (Blair), Soranzo, N. (Nicole), Southam, L. (Lorraine), Spasic-Boskovic, O, Spector, T.D. (Timothy), St. Clair, D. (David), Stalker, J, Stevens, E, Sun, J.P., Surdulescu, G, Suvisaari, J. (Jaana), Syrris, P, R. Taylor (Rohan), Tian, J., Tobin, M.D. (Martin), Valdes, A.M. (Ana Maria), Vandersteen, AM, Vijayarangakannan, P, Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, JTR, Wang, G. B., Wang, J. (Jinxia), Wang, Y. (Ying), Ward, K, Wheeler, E. (Eleanor), Whyte, T, Williams, HJ, Williamson, K.A., Wilson, C, Wilson, S.G. (Scott), Wong, K. (Kenny), Xu, CJ, Yang, J. (Jian), Zhang, F. (Feng), Zhang, P.B., Zheng, H.-F. (Hou-Feng), Smith, A.V. (Davey), Fisher, SE, Wilson, J.F. (James F), Cole, T.J. (T.), Fernandez-Orth, D., Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Jaddoe, V.W.V. (Vincent), Dedoussis, G, Timpson, N.J. (Nicholas), Zeggini, E. (Eleftheria), Vitart, V. (Veronique), Pourcain, B.S. (Beate), Haworth, S., Shapland, C.Y., Hayward, C. (Caroline), Prins, B.P. (Bram), Felix, J.F. (Janine), Medina-Gomez, M.C. (Carolina), Rivadeneira Ramirez, F. (Fernando), Wang, C., Ahluwalia, TS, Vrijheid, M. (Martine), Guxens Junyent, M. (Mònica), Sunyer, J. (Jordi), Tachmazidou, I, Walter, K., Iotchkova, V, Jackson, A.U. (Anne), Cleal, L., Huffmann, J., Min, J. (Josine), Sass, L., Timmers, P, Al Turki, S., Anderson, CA, Anney, R. (Richard), Antony, D, Soler Artigas, M. (Maria), Ayub, M, Bala, S, Barrett, JC, Barroso, I.E. (Inês), Beales, P., Bentham, J, Bhattacharya, S. (Shoumo), Birney, E. (Ewan), Blackwood, D, Bobrow, M, Bochukova, E, Bolton, PF, Bounds, R, Boustred, C, Breen, G. (Gerome), Calissano, M, Carss, K, Charlton, R, Chatterjee, K. (Krishna), Chen, L. (Leslie), Ciampi, A. (Antonio), Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, D.A. (David), Cosgrove, C, Cox, T. (Tessa), Craddock, N.J. (Nick), Crooks, L, Curran, S, Curtis, D. (David), Daly, A, Danecek, P, Day, I.N.M. (Ian), Day-Williams, A, Dominiczak, A. (Anna), Down, T, Li, Y. (Yingrui), Dunham, D.M. (David), Durbin, R, Edkins, T. (Ted), Ekong, R. (Rosemary), Ellis, P. (Paul), Evans, D.M. (David), Farooqi, I.S. (Sadaf), Fitzpatrick, D.R. (David), Flicek, P, Floyd, J. (Jamie), Foley, AR, Franklin, C.S. (Christopher), Futema, M, Gallagher, L. (Louise), Gaunt, T.R. (Tom), Geihs, M, Geschwind, D., Greenwood, J.P. (John), Griffin, H, Grozeva, D. (Detelina), Guo, X.S., Guo, X. (Xiuqing), Gurling, H. (Hugh), Hart, D.J. (Deborah), Hendricks, AE, Holmans, P.A. (Peter), Howie, B, Huang, J. (Jian), Huang, L.R., Hubbard, T., Humphries, S.E. (Steve), Hurles, M.E. (Matthew), Hysi, P.G. (Pirro), Jackson, DK, Jamshidi, Y. (Yalda), Joyce, C, Karczewski, KJ, Kaye, J. (Jane), Keane, T, Kemp, J.P., Kennedy, K. (Karen), Kent, A. (Alistair), Keogh, J, Khawaja, F, van Kogelenberg, M., Kolb-Kokocinski, A, Lachance, G, Langford, C. (Cordelia), Lawson, D, Lee, I. van der, Lek, M, Li, R. (Rui), Li, Y.R. (Yun), Liang, J.Q., Lin, H., Liu, R, Lonnqvist, J, Lopes, LR, Lopes, M., MacArthur, DG, Mangino, M. (Massimo), Marchini, J. (Jonathan), Marenne, G., Maslen, J., Mathieson, I. (Iain), McCarthy, S. (Sean), Mcguffin, P. (Peter), Mcintosh, A.M. (Andrew), McKechanie, AG, McQuillin, A. (Andrew), Memari, Y, Metrustry, S. (Sarah), Migone, N, Mitchison, H.M. (Hannah), Moayyeri, A. (Alireza), Morris, A.D. (Andrew), Morris, J, Muddyman, D, Muntoni, F., Northstone, K. (Kate), O'Donovan, M. (Michael), O'Rahilly, S. (Stephen), Onoufriadis, A, Oualkacha, K., Owen, M.J., Palotie, A. (Aarno), Panoutsopoulou, K, Parker, V., Parr, D., Paternoster, L. (Lavinia), Paunio, T, Payne, F. (Felicity), Payne, SJ, Perry, J.B. (John), Pietiläinen, O.P.H. (Olli), Plagnol, V, Pollitt, RC, Porteous, D.J. (David J.), Povey, S. (Sue), Quail, MA, Quaye, L. (Lydia), Raymond, FL, Rehnström, K. (Karola), Richards, J.B. (Brent), Ridout, CK, Ring, S.M. (Susan), Ritchie, GRS, Roberts, N. (Nicola), Robinson, RL, Savage, D.B. (David), Scambler, P., Schiffels, S, Schmidts, M, Schoenmakers, N. (Nadia), Scott, RH, Semple, R.K. (Robert), Serra, E, Sharp, S.I., Shaw, A. (Alison), Shihab, HA, Shin, S.-Y., Skuse, D, Small, K.S. (Kerrin), Smee, C, Smith, B.H. (Blair), Soranzo, N. (Nicole), Southam, L. (Lorraine), Spasic-Boskovic, O, Spector, T.D. (Timothy), St. Clair, D. (David), Stalker, J, Stevens, E, Sun, J.P., Surdulescu, G, Suvisaari, J. (Jaana), Syrris, P, R. Taylor (Rohan), Tian, J., Tobin, M.D. (Martin), Valdes, A.M. (Ana Maria), Vandersteen, AM, Vijayarangakannan, P, Visscher, P.M. (Peter), Wain, L.V. (Louise), Walters, JTR, Wang, G. B., Wang, J. (Jinxia), Wang, Y. (Ying), Ward, K, Wheeler, E. (Eleanor), Whyte, T, Williams, HJ, Williamson, K.A., Wilson, C, Wilson, S.G. (Scott), Wong, K. (Kenny), Xu, CJ, Yang, J. (Jian), Zhang, F. (Feng), Zhang, P.B., Zheng, H.-F. (Hou-Feng), Smith, A.V. (Davey), Fisher, SE, Wilson, J.F. (James F), Cole, T.J. (T.), Fernandez-Orth, D., Bønnelykke, K. (Klaus), Bisgaard, H. (Hans), Pennell, C.E. (Craig), Jaddoe, V.W.V. (Vincent), Dedoussis, G, Timpson, N.J. (Nicholas), Zeggini, E. (Eleftheria), Vitart, V. (Veronique), and Pourcain, B.S. (Beate) more...
- Abstract
Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for lowfrequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carrie more...
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- 2019
- Full Text
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24. CiliaCarta: An integrated and validated compendium of ciliary genes
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Dam, T.J.P. van, Kennedy, J., Lee, R. van der, Vrieze, E. de, Wunderlich, K.A., Rix, S., Dougherty, G.W., Lambacher, N.J., Li, C., Jensen, V.L., Leroux, M.R., Hjeij, R., Horn, N., Texier, Y., Wissinger, Y., Reeuwijk, J. van, Wheway, G., Knapp, B., Scheel, J.F., Franco, B., Mans, D.A., WIjk, E. van, Kepes, F., Slaats, G.G., Toedt, G., Kremer, H., Omran, H., Szymanska, K., Koutroumpas, K., Ueffing, M., Nguyen, T.T.M., Letteboer, S.J.F., Oud, M.M., Beersum, S.E.C. van, Schmidts, M., Beales, P.L., Lu, Q., Giles, R.H., Szklarczyk, R., Russell, R.B., Gibson, T.J., Johnson, C.A., Blacque, O.E., Wolfrum, U., Boldt, K., Roepman, R., Hernandez-Hernandez, V., Huynen, M.A., Dam, T.J.P. van, Kennedy, J., Lee, R. van der, Vrieze, E. de, Wunderlich, K.A., Rix, S., Dougherty, G.W., Lambacher, N.J., Li, C., Jensen, V.L., Leroux, M.R., Hjeij, R., Horn, N., Texier, Y., Wissinger, Y., Reeuwijk, J. van, Wheway, G., Knapp, B., Scheel, J.F., Franco, B., Mans, D.A., WIjk, E. van, Kepes, F., Slaats, G.G., Toedt, G., Kremer, H., Omran, H., Szymanska, K., Koutroumpas, K., Ueffing, M., Nguyen, T.T.M., Letteboer, S.J.F., Oud, M.M., Beersum, S.E.C. van, Schmidts, M., Beales, P.L., Lu, Q., Giles, R.H., Szklarczyk, R., Russell, R.B., Gibson, T.J., Johnson, C.A., Blacque, O.E., Wolfrum, U., Boldt, K., Roepman, R., Hernandez-Hernandez, V., and Huynen, M.A. more...
- Abstract
Contains fulltext : 204265.pdf (publisher's version ) (Open Access), The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/. more...
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- 2019
25. Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
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Rehman, Atteeq U., Najafi, Maryam, Kambouris, Marios, Al-Gazali, Lihadh, Makrythanasis, Periklis, Rad, Abolfazl, Bakey, Z., Wu, K.M., Yang, Yaping, Schmidts, M., Rehman, Atteeq U., Najafi, Maryam, Kambouris, Marios, Al-Gazali, Lihadh, Makrythanasis, Periklis, Rad, Abolfazl, Bakey, Z., Wu, K.M., Yang, Yaping, and Schmidts, M. more...
- Abstract
Contains fulltext : 201369.pdf (publisher's version ) (Open Access)
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- 2019
26. Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
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Rehman, AU, Najafi, M, Kambouris, M, Al-Gazali, L, Makrythanasis, P, Rad, A, Maroofian, R, Rajab, A, Stark, Z, Hunter, JV, Bakey, Z, Tokita, MJ, He, W, Vetrini, F, Petersen, A, Santoni, FA, Hamamy, H, Wu, K, Al-Jasmi, F, Helmstaedter, M, Arnold, SJ, Xia, F, Richmond, C, Liu, P, Karimiani, EG, Madani, GK, Lunke, S, El-Shanti, H, Eng, CM, Antonarakis, SE, Hertecant, J, Walkiewicz, M, Yang, Y, Schmidts, M, Rehman, AU, Najafi, M, Kambouris, M, Al-Gazali, L, Makrythanasis, P, Rad, A, Maroofian, R, Rajab, A, Stark, Z, Hunter, JV, Bakey, Z, Tokita, MJ, He, W, Vetrini, F, Petersen, A, Santoni, FA, Hamamy, H, Wu, K, Al-Jasmi, F, Helmstaedter, M, Arnold, SJ, Xia, F, Richmond, C, Liu, P, Karimiani, EG, Madani, GK, Lunke, S, El-Shanti, H, Eng, CM, Antonarakis, SE, Hertecant, J, Walkiewicz, M, Yang, Y, and Schmidts, M more...
- Abstract
Next-generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co-immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin-488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway. more...
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- 2019
27. 'Good habits fade, bad habits develop' - Lehr-, Lern- und Prüfungsstrategien im Umgang mit der ärztlichen Sozialisation am Arbeitsplatz [Bericht über Entwicklungsprozess]
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Schmidts, M. and Wieser, M.
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Problem: Im KL-Medizincurriculum unterrichten wir medizinische Kompetenzen (CanMeds) in Fallgesprächen, Rollenspielen mit simulierten Patienten oder im Skills-Labor. In der klinischen Praxis erleben unsere Studierenden dann gegebenenfalls eine Diskrepanz zwischen dem „idealen Weg“,[zum vollständigen Text gelangen Sie über die oben angegebene URL], Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA) more...
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- 2018
28. Identifizieren von leistungsgefährdeten Studierenden anhand Detailanalyse vorangegangener Prüfungsleistungen [Bericht über Entwicklungsprozess]
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Wieser, M. and Schmidts, M.
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Problemstellung/Ziele: Die Vorhersage studentischer Lernerfolge ist in der Prävention von Studienabbrüchen oder Studienzeitverlängerungen wesentlich [ref:1]. Leistungsabfallgefährdete Studierende sollen frühzeitig identifiziert und ein weiterer Abfall durch gezielte[zum vollständigen Text gelangen Sie über die oben angegebene URL], Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA) more...
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- 2018
29. High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations
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Shoemark, A, Moya, E, Hirst, RA, Patel, MP, Robson, EA, Hayward, J, Scully, J, Fassad, MR, Lamb, W, Schmidts, M, Dixon, M, Patel-King, RS, Rogers, AV, Rutman, A, Jackson, CL, Goggin, P, Rubbo, B, Ollosson, S, Carr, S, Walker, W, Adler, B, Loebinger, MR, Wilson, R, Bush, A, Williams, H, Boustred, C, Jenkins, L, Sheridan, E, Chung, EMK, Watson, CM, Cullup, T, Lucas, JS, Kenia, P, O’Callaghan, C, King, SM, Hogg, C, and Mitchison, HM more...
- Subjects
otorhinolaryngologic diseases - Abstract
Rationale Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal. Objectives To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive. Methods Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay. Results Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed. Conclusions The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests. more...
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- 2018
30. Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility
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Ta-Shma, Asaf, Hjeij, R., Perles, Zeev, Dougherty, G.W., Abu Zahira, Ibrahim, Letteboer, S.J.F., Antony, D., Schmidts, M., Roepman, R., Elpeleg, Orly, Omran, H., Ta-Shma, Asaf, Hjeij, R., Perles, Zeev, Dougherty, G.W., Abu Zahira, Ibrahim, Letteboer, S.J.F., Antony, D., Schmidts, M., Roepman, R., Elpeleg, Orly, and Omran, H. more...
- Abstract
Contains fulltext : 196394.pdf (publisher's version ) (Open Access)
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- 2018
31. Primary cilia-regulated transcriptome in the renal collecting duct
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Mohammed, S.G., Arjona, F.J., Verschuren, E.H.J., Bakey, Z., Alkema, W.B.L., Hijum, S.A.F.T. van, Schmidts, M., Bindels, R.J.M., Hoenderop, J.G.J., Mohammed, S.G., Arjona, F.J., Verschuren, E.H.J., Bakey, Z., Alkema, W.B.L., Hijum, S.A.F.T. van, Schmidts, M., Bindels, R.J.M., and Hoenderop, J.G.J. more...
- Abstract
Contains fulltext : 192636.pdf (publisher's version ) (Closed access)
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- 2018
32. High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations
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Shoemark, A., Moya, Eduardo, Hirst, Robert A., Patel, M.P., Robson, Evelyn A., Hayward, J., Schmidts, M., Hogg, C., Mitchison, H.M., Shoemark, A., Moya, Eduardo, Hirst, Robert A., Patel, M.P., Robson, Evelyn A., Hayward, J., Schmidts, M., Hogg, C., and Mitchison, H.M. more...
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Item does not contain fulltext
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- 2018
33. Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis
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Oud, M.M., Latour, B.L., Bakey, Z., Letteboer, S.J., Lugtenberg, D., Wu, K.M., Cornelissen, E.A.M., Yntema, H.G., Schmidts, M., Roepman, R., Bongers, E.M.H.F., Oud, M.M., Latour, B.L., Bakey, Z., Letteboer, S.J., Lugtenberg, D., Wu, K.M., Cornelissen, E.A.M., Yntema, H.G., Schmidts, M., Roepman, R., and Bongers, E.M.H.F. more...
- Abstract
Contains fulltext : 199977.pdf (publisher's version ) (Open Access), Background: Mainzer-Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions: By combining the clinical, genetic, and functional data from this study, we could conclud more...
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- 2018
34. Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects
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Loges, N.T., Antony, D., Maver, Ales, Deardorff, M.A., Gulec, Elif Yylmaz, Gezdirici, A., Wu, K.M., Bakey, Z., Brunner, H.G., Omran, H., Schmidts, M., Loges, N.T., Antony, D., Maver, Ales, Deardorff, M.A., Gulec, Elif Yylmaz, Gezdirici, A., Wu, K.M., Bakey, Z., Brunner, H.G., Omran, H., and Schmidts, M. more...
- Abstract
Contains fulltext : 199518.pdf (Publisher’s version ) (Open Access)
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- 2018
35. Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms
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Höben, I.M., Hjeij, Rim, Olbrich, H., Dougherty, G.W., Noethe-Menchen, Tabea, Aprea, I., Wu, K.M., Bakey, Z., Schmidts, M., Loges, N.T., Omran, H., Höben, I.M., Hjeij, Rim, Olbrich, H., Dougherty, G.W., Noethe-Menchen, Tabea, Aprea, I., Wu, K.M., Bakey, Z., Schmidts, M., Loges, N.T., and Omran, H. more...
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Item does not contain fulltext
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- 2018
36. Expanding the clinical phenotype of IARS2-related mitochondrial disease
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Vona, Barbara, Maroofian, Reza, Bellacchio, Emanuele, Najafi, Maryam, Thompson, Kyle, Alahmad, Ahmad, Schmidts, M., Taylor, Robert W., Karimiani, Ehsan Ghayoor, Vona, Barbara, Maroofian, Reza, Bellacchio, Emanuele, Najafi, Maryam, Thompson, Kyle, Alahmad, Ahmad, Schmidts, M., Taylor, Robert W., and Karimiani, Ehsan Ghayoor more...
- Abstract
Contains fulltext : 198289.pdf (publisher's version ) (Open Access)
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- 2018
37. Identifizieren von leistungsgefährdeten Studierenden anhand Detailanalyse vorangegangener Prüfungsleistungen [Bericht über Entwicklungsprozess]
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Wieser, M, Schmidts, M, Wieser, M, and Schmidts, M
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- 2018
38. 'Good habits fade, bad habits develop' - Lehr-, Lern- und Prüfungsstrategien im Umgang mit der ärztlichen Sozialisation am Arbeitsplatz [Bericht über Entwicklungsprozess]
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Schmidts, M, Wieser, M, Schmidts, M, and Wieser, M
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- 2018
39. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
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Hendricks, A.E. Bochukova, E.G. Marenne, G. Keogh, J.M. Atanassova, N. Bounds, R. Wheeler, E. Mistry, V. Henning, E. Körner, A. Muddyman, D. McCarthy, S. Hinney, A. Hebebrand, J. Scott, R.A. Langenberg, C. Wareham, N.J. Surendran, P. Howson, J.M. Butterworth, A.S. Danesh, J. Nordestgaard, Bø.G. Nielsen, S.F. Afzal, S. Papadia, S. Ashford, S. Garg, S. Millhauser, G.L. Palomino, R.I. Kwasniewska, A. Tachmazidou, I. O'Rahilly, S. Zeggini, E. Barroso, I. Farooqi, I.S. Benzeval, M. Burton, J. Buck, N. Jäckle, A. Kumari, M. Laurie, H. Lynn, P. Pudney, S. Rabe, B. Wolke, D. Overvad, K. Tjønneland, A. Clavel-Chapelon, F. Kaaks, R. Boeing, H. Trichopoulou, A. Ferrari, P. Palli, D. Krogha, V. Panico, S. Tuminoa, R. Matullo, G. Boer, J. Van Der Schouw, Y. Weiderpass, E. Quiros, J.R. Sánchez, M.-J. Navarro, C. Moreno-Iribas, C. Arriola, L. Melander, O. Wennberg, P. Key, T.J. Riboli, E. Turki, S.A. Anderson, C.A. Anney, R. Antony, D. Soler Artigas, M. Ayub, M. Bala, S. Barrett, J.C. Beales, P. Bentham, J. Bhattacharyaa, S. Birney, E. Blackwooda, D. Bobrow, M. Bolton, P.F. Boustred, C. Breen, G. Calissanoa, M. Carss, K. Charlton, R. Chatterjee, K. Chen, L. Ciampia, A. Cirak, S. Clapham, P. Clement, G. Coates, G. Coccaa, M. Collier, D.A. Cosgrove, C. Coxa, T. Craddock, N. Crooks, L. Curran, S. Curtis, D. Daly, A. Danecek, P. Day, I.N.M. Day-Williams, A. Dominiczak, A. Down, T. Du, Y. Dunham, I. Durbin, R. Edkins, S. Ekong, R. Ellis, P. Evansa, D.M. Fitzpatrick, D.R. Flicek, P. Floyd, J. Foley, A.R. Franklin, C.S. Futema, M. Gallagher, L. Gaunt, T.R. Geihs, M. Geschwind, D. Greenwood, C.M.T. Griffin, H. Grozeva, D. Guo, X. Guo, X. Gurling, H. Hart, D. Holmans, P. Howie, B. Huang, J. Huang, L. Hubbard, T. Humphries, S.E. Hurles, M.E. Hysi, P. Iotchkova, V. Jackson, D.K. Jamshidi, Y. Joyce, C. Karczewski, K.J. Kaye, J. Keane, T. Kemp, J.P. Kennedy, K. Kent, A. Khawaja, F. Van Kogelenberg, M. Kolb-Kokocinski, A. Lachance, G. Langford, C. Lawson, D. Lee, I. Lek, M. Li, R. Li, Y. Liang, J. Lin, H. Liu, R. Lönnqvist, J. Lopes, L.R. Lopes, M. MacArthur, D.G. Mangino, M. Marchini, J. Maslen, J. Mathieson, I. McGuffin, P. McIntosh, A.M. McKechanie, A.G. McQuillin, A. Memari, Y. Metrustry, S. Migone, N. Min, J.L. Mitchison, H.M. Moayyeri, A. Morris, A. Morris, J. Muntoni, F. Northstone, K. O'Donovan, M.C. Onoufriadis, A. Oualkacha, K. Owen, M.J. Palotie, A. Panoutsopoulou, K. Parker, V. Parr, J.R. Paternoster, L. Paunio, T. Payne, F. Payne, S.J. Perry, J.R.B. Pietilainen, O. Plagnol, V. Pollitt, R.C. Porteous, D.J. Povey, S. Quail, M.A. Quaye, L. Raymond, F.L. Rehnström, K. Richards, J.B. Ridout, C.K. Ring, S. Ritchie, G.R.S. Roberts, N. Robinson, R.L. Savage, D.B. Scambler, P. Schiffels, S. Schmidts, M. Schoenmakers, N. Scott, R.H. Semple, R.K. Serra, E. Sharp, S.I. Shaw, A. Shihab, H.A. Shin, S.-Y. Skuse, D. Small, K.S. Smee, C. Smith, B.H. Davey Smith, G. Soranzo, N. Southam, L. Spasic-Boskovic, O. Spector, T.D. St Clair, D. St Pourcain, B. Stalker, J. Stevens, E. Sun, J. Surdulescu, G. Suvisaari, J. Syrris, P. Taylor, R. Tian, J. Timpson, N.J. Tobin, M.D. Valdes, A.M. Vandersteen, A.M. Vijayarangakannan, P. Visscher, P.M. Wain, L.V. Walter, K. Walters, J.T.R. Wang, G. Wang, J. Wang, Y. Ward, K. Whyte, T. Williams, H.J. Williamson, K.A. Wilson, C. Wilson, S.G. Wong, K. Xu, C. Yang, J. Zhang, F. Zhang, P. Zheng, H.-F. more...
- Abstract
Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. © 2017 The Author(s). more...
- Published
- 2017
40. Mutation in the CCDC114 gene causes Primary Ciliary Dyskinesia with normal fertility in the isolated Volendam population
- Author
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Paff, T., Onoufriadis, A., Anthony, D., Shoemark, A., Micha, D., Kuyt, B., Schmidts, M., Petridi, S., Dankert-Roelse, J.E., Haarman, E.G., Daniels, J.M.A., Emes, R.D., Wilson, R., Hoggs, C., Scambler, P.J., Chung, E.M.K., Mitchison, H.M., Pals, G., and UK10K more...
- Published
- 2013
- Full Text
- View/download PDF
41. Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects.
- Author
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Paff, T., Loges, N.T., Aprea, I., Wu, K., Bakey, Z., Haarman, E.G., Daniels, J.M., Sistermans, E.A., Bogunovic, N., Dougherty, G.W., Höben, I.M., Große-Onnebrink, J., Matter, A., Olbrich, H., Werner, C., Pals, G., Schmidts, M., Omran, H., Micha, D., Paff, T., Loges, N.T., Aprea, I., Wu, K., Bakey, Z., Haarman, E.G., Daniels, J.M., Sistermans, E.A., Bogunovic, N., Dougherty, G.W., Höben, I.M., Große-Onnebrink, J., Matter, A., Olbrich, H., Werner, C., Pals, G., Schmidts, M., Omran, H., and Micha, D. more...
- Abstract
Contains fulltext : 169756.pdf (Publisher’s version ) (Open Access)
- Published
- 2017
42. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.
- Author
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Olcese, C., Patel, M.P., Shoemark, A., Kiviluoto, S., Legendre, M., Williams, H.J., Vaughan, C.K., Hayward, J., Goldenberg, A., Emes, R.D., Munye, M.M., Dyer, L., Cahill, T., Bevillard, J., Gehrig, C., Guipponi, M., Chantot, S., Duquesnoy, P., Thomas, L., Jeanson, L., Copin, B., Tamalet, A., Thauvin-Robinet, C., Papon, J.F., Garin, A., Pin, I., Vera, G., Aurora, P., Fassad, M.R., Jenkins, L., Boustred, C., Cullup, T., Dixon, M., Onoufriadis, A., Bush, A., Chung, E.M., Antonarakis, S.E., Loebinger, M.R., Wilson, R., Armengot, M., Escudier, E., Hogg, C., Amselem, S., Sun, Z., Bartoloni, L., Blouin, J.L., Mitchison, H.M., Schmidts, M., et al., Olcese, C., Patel, M.P., Shoemark, A., Kiviluoto, S., Legendre, M., Williams, H.J., Vaughan, C.K., Hayward, J., Goldenberg, A., Emes, R.D., Munye, M.M., Dyer, L., Cahill, T., Bevillard, J., Gehrig, C., Guipponi, M., Chantot, S., Duquesnoy, P., Thomas, L., Jeanson, L., Copin, B., Tamalet, A., Thauvin-Robinet, C., Papon, J.F., Garin, A., Pin, I., Vera, G., Aurora, P., Fassad, M.R., Jenkins, L., Boustred, C., Cullup, T., Dixon, M., Onoufriadis, A., Bush, A., Chung, E.M., Antonarakis, S.E., Loebinger, M.R., Wilson, R., Armengot, M., Escudier, E., Hogg, C., Amselem, S., Sun, Z., Bartoloni, L., Blouin, J.L., Mitchison, H.M., Schmidts, M., and et al. more...
- Abstract
Contains fulltext : 174892.pdf (publisher's version ) (Open Access), By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins. more...
- Published
- 2017
43. Exome sequencing for the differential diagnosis of ciliary chondrodysplasias: Example of a WDR35 mutation case and review of the literature
- Author
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Antony, D., Nampoory, N., Bacchelli, C., Melhem, M., Wu, K., James, C.T., Beales, P.L., Hubank, M., Thomas, D, Mashankar, A., Behbehani, K., Schmidts, M., Alsmadi, O., Antony, D., Nampoory, N., Bacchelli, C., Melhem, M., Wu, K., James, C.T., Beales, P.L., Hubank, M., Thomas, D, Mashankar, A., Behbehani, K., Schmidts, M., and Alsmadi, O. more...
- Abstract
Contains fulltext : 250369.pdf (Author’s version preprint ) (Open Access) Contains fulltext : 250369.pdf (Publisher’s version ) (Closed access)
- Published
- 2017
44. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
- Author
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Wheway, G, Schmidts, M, Mans, DA, Szymanska, K, Nguyen, TT, Racher, H, Phelps, IG, Toedt, G, Kennedy, J, Wunderlich, KA, Sorusch, N, Abdelhamed, ZA, Natarajan, S, Herridge, W, van Reeuwijk, J, Horn, N, Boldt, K, Parry, DA, Letteboer, SJ, Roosing, S, Adams, M, Bell, SM, Bond, J, Higgins, J, Morrison, EE, Tomlinson, DC, Slaats, GG, van Dam, TJ, Huang, L, Kessler, K, Giessl, A, Logan, CV, Boyle, EA, Shendure, J, Anazi, S, Aldahmesh, M, Al Hazzaa, S, Hegele, RA, Ober, C, Frosk, P, Mhanni, AA, Chodirker, BN, Chudley, AE, Lamont, R, Bernier, FP, Beaulieu, CL, Gordon, P, Pon, RT, Donahue, C, Barkovich, AJ, Wolf, L, Toomes, C, Thiel, CT, Boycott, KM, McKibbin, M, Inglehearn, CF, UK10K Consortium, University ofWashington Center forMendelian Genomics, Stewart, F, Omran, H, Huynen, MA, Sergouniotis, PI, Alkuraya, FS, Parboosingh, JS, Innes, AM, Willoughby, CE, Giles, RH, Webster, AR, Ueffing, M, Blacque, O, Gleeson, JG, Wolfrum, U, Beales, PL, Gibson, T, Doherty, D, Mitchison, HM, Roepman, R, and Johnson, CA more...
- Abstract
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease. more...
- Published
- 2015
45. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
- Author
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Schmidts, M, Hou, Y, Cortés, CR, Mans, DA, Huber, C, Boldt, K, Patel, M, Van Reeuwijk, J, Plaza, JM, Van Beersum, SEC, Yap, ZM, Letteboer, SJF, Taylor, SP, Herridge, W, Johnson, CA, Scambler, PJ, Ueffing, M, Kayserili, H, Krakow, D, King, SM, Beales, PL, Al-Gazali, L, Wicking, C, Cormier-Daire, V, Roepman, R, Mitchison, HM, Witman, GB, UK 10K, Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository more...
- Subjects
Ellis-Van Creveld Syndrome ,Dyneins ,Penetrance ,Cytoskeletal Proteins ,Mice ,HEK293 Cells ,Flagella ,Gene Knockdown Techniques ,Mutation ,Animals ,Humans ,sense organs ,Chlamydomonas reinhardtii ,Zebrafish - Abstract
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. more...
- Published
- 2015
46. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies
- Author
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Shaheen, R., Schmidts, M., Faqeih, E., Hashem, A., Lausch, E., Holder, I., Superti-Furga, A., Mitchison, H.M., Almoisheer, A., Alamro, R., Alshiddi, T., Alzahrani, F., Beales, P.L., Alkuraya, F.S., and UK10K Consortium more...
- Subjects
Male ,Ellis-Van Creveld Syndrome ,Molecular Sequence Data ,Mutation, Missense ,Saudi Arabia ,Cell Cycle Proteins ,Bone and Bones ,Cohort Studies ,Animals ,Humans ,Amino Acid Sequence ,Cilia ,Zebrafish ,Centrioles ,Chromosome Mapping ,Infant ,Articles ,Fibroblasts ,Magnetic Resonance Imaging ,Pedigree ,Europe ,Disease Models, Animal ,Phenotype ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Genetic Loci ,Chromosomes, Human, Pair 5 ,Female ,Genome-Wide Association Study - Abstract
Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies. more...
- Published
- 2015
47. Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum
- Author
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Maria, M., Lamers, I.J.C., Schmidts, M., Ajmal, M., Jaffar, S., Ullah, E., Mustafa, B., Ahmad, S., Nazmutdinova, K., Hoskins, B., Wijk, E. van, Koster-Kamphuis, L., Khan, M.I., Beales, P.L., Cremers, F.P.M., Roepman, R., Azam, M., Arts, H.H., Qamar, R., Maria, M., Lamers, I.J.C., Schmidts, M., Ajmal, M., Jaffar, S., Ullah, E., Mustafa, B., Ahmad, S., Nazmutdinova, K., Hoskins, B., Wijk, E. van, Koster-Kamphuis, L., Khan, M.I., Beales, P.L., Cremers, F.P.M., Roepman, R., Azam, M., Arts, H.H., and Qamar, R. more...
- Abstract
Contains fulltext : 167825.pdf (publisher's version ) (Open Access), Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell's signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician's ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals. more...
- Published
- 2016
48. Accuracy of diagnostic testing in primary ciliary dyskinesia: are we there yet?
- Author
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Haarman, E.G., Schmidts, M., Haarman, E.G., and Schmidts, M.
- Abstract
Item does not contain fulltext
- Published
- 2016
49. Curriculum mapping - den Ist-Zustand sichtbar machen
- Author
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Bayha, E, Minder, S, Schmidts, M, Frey, P, Bayha, E, Minder, S, Schmidts, M, and Frey, P
- Published
- 2016
50. Kick-off Workshop: Publizieren und Teilen von 'guter Lehre'. Distributionskanäle, Qualitätssicherung, Anreizsysteme
- Author
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Schmidts, M, Brem, B, Woermann, U, Schmidts, M, Brem, B, and Woermann, U
- Published
- 2016
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