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Your search keyword '"Kasteleijn, E."' showing total 2 results
Start Over Author "Kasteleijn, E." Topic 0302 clinical medicine
2 results on '"Kasteleijn, E."'

1. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

Author

Flavia Palombo, Maarten Fornerod, Grazia M.S. Mancini, Joseph G. Gleeson, Lily Bazak, Esmee Kasteleijn, Natalia Ordonez-Herrera, Milena Laure-Kamionowska, Fowzan S. Alkuraya, Pawel Gawlinski, William B. Dobyns, Mariasavina Severino, Marjolein H G Dremmen, Marco Seri, Marie Claire Y. de Wit, Robert B. Hufnagel, Ghayda Mirzaa, Laura Vandervore, Rachel Schot, Maarten H. Lequin, Lina Basel-Salmon, Arndt Rolfs, Robert J. Hopkin, Ahmed Al Fares, Nicola Brunetti-Pierri, Bella Davidov, Gerarda Cappuccio, Maria Teresa Divizia, Rolf W. Stottmann, Daphne J. Smits, Aida M. Bertoli-Avella, Wojciech Wiszniewski, Damir Musaev, Valentina Stanley, Hanah Akleh, Peter Bauer, Amal Alhashem, Martina Wilke, Jeroen Demmers, Malak Al Ghamdi, Marjon van Slegtenhorst, Pasquale Striano, Mees van der Ent, Pamela Magini, Tommaso Pippucci, Marta Columbaro, Maha S. Zaki, Anna Jansen, Deema Aljeaid, Peter J. van der Spek, Noa Ruhrman Shahar, Frans W. Verheijen, Clinical Biology, Clinical sciences, Faculty of Medicine and Pharmacy, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, Magini, P., Smits, D. J., Vandervore, L., Schot, R., Columbaro, M., Kasteleijn, E., van der Ent, M., Palombo, Francesco, Lequin, M. H., Dremmen, M., de Wit, M. C. Y., Severino, M., Divizia, M. T., Striano, P., Ordonez-Herrera, N., Alhashem, A., Al Fares, A., Al Ghamdi, M., Rolfs, A., Bauer, P., Demmers, J., Verheijen, F. W., Wilke, M., van Slegtenhorst, M., van der Spek, P. J., Seri, M., Jansen, A. C., Stottmann, R. W., Hufnagel, R. B., Hopkin, R. J., Aljeaid, D., Wiszniewski, W., Gawlinski, P., Laure-Kamionowska, M., Alkuraya, F. S., Akleh, H., Stanley, V., Musaev, D., Gleeson, J. G., Zaki, M. S., Brunetti-Pierri, N., Cappuccio, G., Davidov, B., Basel-Salmon, L., Bazak, L., Shahar, N. R., Bertoli-Avella, A., Mirzaa, G. M., Dobyns, W. B., Pippucci, T., Fornerod, M., Mancini, G. M. S., Clinical Genetics, Clinical Chemistry, Cell biology, Radiology & Nuclear Medicine, Neurology, Biochemistry, Pathology, Magini P., Smits D.J., Vandervore L., Schot R., Columbaro M., Kasteleijn E., van der Ent M., Palombo F., Lequin M.H., Dremmen M., de Wit M.C.Y., Severino M., Divizia M.T., Striano P., Ordonez-Herrera N., Alhashem A., Al Fares A., Al Ghamdi M., Rolfs A., Bauer P., Demmers J., Verheijen F.W., Wilke M., van Slegtenhorst M., van der Spek P.J., Seri M., Jansen A.C., Stottmann R.W., Hufnagel R.B., Hopkin R.J., Aljeaid D., Wiszniewski W., Gawlinski P., Laure-Kamionowska M., Alkuraya F.S., Akleh H., Stanley V., Musaev D., Gleeson J.G., Zaki M.S., Brunetti-Pierri N., Cappuccio G., Davidov B., Basel-Salmon L., Bazak L., Shahar N.R., Bertoli-Avella A., Mirzaa G.M., Dobyns W.B., Pippucci T., Fornerod M., and Mancini G.M.S.

Subjects
Male, 0301 basic medicine, Microcephaly, Ceramide, RNA Splicing, Mitosis, Cell fate determination, Biology, Endoplasmic Reticulum, Article, arthrogryposis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, medicine, Humans, Cell Lineage, microcephaly, Nuclear pore, Child, SMPD4, Genetics (clinical), Arthrogryposis, arthrogryposi, neutral-sphingomyelinase, Gene Expression Profiling, Autophagy, medicine.disease, Sphingolipid, Pedigree, NET13, Cell biology, HEK293 Cells, Sphingomyelin Phosphodiesterase, 030104 developmental biology, chemistry, Neurodevelopmental Disorders, Female, medicine.symptom, Sphingomyelin, 030217 neurology & neurosurgery
Abstract

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

Published
2019

2. Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Author

Marianne L. T. van der Sterre, Rachel Schot, Peter J. van der Spek, Daphne Heijsman, Leontine van Unen, Gert-Jan Kremers, Martyna M. Grochowska, Grazia M.S. Mancini, Laura Vandervore, Roy Masius, Gerben J. Schaaf, Martina Wilke, Nadia Bahi-Buisson, Anna Grandone, Renske Oegema, Anna Jansen, Patrick Rump, Arie van Haeringen, Tugba Kalayci, Frans W. Verheijen, Katrien Stouffs, Peter Elfferich, Els A. J. Peeters, Esmee Kasteleijn, Anton J. van Essen, Umut Altunoglu, Alexander Gheldof, Dick H. W. Dekkers, Johan A. Slotman, Jeroen Demmers, Raymond A. Poot, WB Dobyns, Vandervore, L. V., Schot, R., Kasteleijn, E., Oegema, R., Stouffs, K., Gheldof, A., Grochowska, M. M., Van Der Sterre, M. L. T., Van Unen, L. M. A., Wilke, M., Elfferich, P., Van Der Spek, P. J., Heijsman, D., Grandone, A., Demmers, J. A. A., Dekkers, D. H. W., Slotman, J. A., Kremers, G. -J., Schaaf, G. J., Masius, R. G., Van Essen, A. J., Rump, P., Van Haeringen, A., Peeters, E., Altunoglu, U., Kalayci, T., Poot, R. A., Dobyns, W. B., Bahi-Buisson, N., Verheijen, F. W., Jansen, A. C., Mancini, G. M. S., Clinical Genetics, Pathology, Molecular Genetics, Cell biology, Clinical sciences, Faculty of Medicine and Pharmacy, Medical Genetics, Reproduction and Genetics, Faculty of Psychology and Educational Sciences, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, and Pediatrics

Subjects
0301 basic medicine, Microcephaly, MIGRATION, MYH10, Clinical Neurology, Lissencephaly, PRIMARY CILIA, Cell Cycle Proteins, Biology, medicine.disease_cause, NONMUSCLE MYOSIN-II, 03 medical and health sciences, 0302 clinical medicine, Ciliogenesis, medicine, Polymicrogyria, Basal body, Humans, mitosis, Mutation, mitosi, DEFECTS, Original Articles, medicine.disease, POINT MUTATION, Cell biology, 030104 developmental biology, Phenotype, Centrosome, Neurology (clinical), centrosome amplification, Carrier Proteins, Multipolar spindles, RTTN, 030217 neurology & neurosurgery
Abstract

See Uzquiano and Francis (doi:10.1093/brain/awz048) for a scientific commentary on this article. Mutations in RTTN, which encodes Rotatin, give rise to various brain malformations. Vandervore et al. reveal mitotic failure, aneuploidy, apoptosis and defective ciliogenesis in patient cells. Rotatin binds to myosin subunits in the leading edge of human neurons, which may explain the proliferation and migration defects observed., Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.

Published
2019

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