10 results on '"Vandervore L."'
Search Results
2. Loss of neutral sphingomyelinase-3 (SMPD4) links neurodevelopmental disorders to cell cycle and nuclear envelope anomalies
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Smits, D. J., Magini, P., Vandervore, L., Schot, R., Columbaro, M., Kasteleijn, E., Ent, M., Palombo, F., Iommarini, L., Lequin, M. H., Porcelli, A. M., Govaert, P., Dremmen, M., Wit, M. C. Y., Severino, M., Divizia, M. T., Ordonez-Herrera, N., Alhashem, A., Al Fares, A., Al Ghamdi, M., Rolfs, A., Bauer, P., Demmers, J., Verheijen, F., Wilke, M., Slegtenhorst, M., Spek, P., Jansen, A., Rolf Stottmann, Hufnagel, R., Hopkin, R., Aljeaid, D., Wiszniewski, W., Gawlinski, P., Dobyns, W. B., Seri, M., Pippucci, T., Fornerod, M., and Mancini, G. M. S. more...
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3. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis
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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. more...
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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. more...
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- 2019
4. Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics
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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 more...
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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. more...
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- 2019
5. Aztreonam-avibactam synergy, a validation and comparison of diagnostic tools.
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Verschelden G, Noeparast M, Stoefs A, Van Honacker E, Vandoorslaer K, Vandervore L, Olbrecht M, Van Damme K, Demuyser T, Piérard D, and Wybo I
- Abstract
Introduction: Antimicrobial resistance is a growing problem that necessitates the development of new therapeutic options. Cefiderocol and aztreonam (AT) are often the last active β-lactams for treating metallo-β-lactamases (MBL)-producing Gram-negative bacilli. In these difficult-to-treat bacterial strains, AT resistance is frequently attributed to the co-occurrence of other resistance mechanisms. In the case of β-lactamases they can often be inhibited by avibactam. In the present study, we evaluated the use of the double-disc synergy test (DDST) as a screening tool for the detection of synergy between AT-avibactam (ATA). We validated both the Gradient Diffusion Strips (GDSs) superposition method and the commercially available Liofilchem's ATA GDS., Materials and Methods: We tested AT susceptibility in combination with ceftazidime-avibactam for 65 strains, including 18 Serine-β-Lactamase (SBL)- and 24 MBL-producing Enterobacterales , 12 MBL-producing P. aeruginosa , and 11 S. maltophilia isolates. Interpretation was done with EUCAST breakpoints (version 13.0), AT breakpoints being used for ATA. The accuracy and validity of the GDSs superposition method and ATA GDS were evaluated using an AT GDS applied on Mueller Hinton Agar plates supplemented with avibactam (MH-AV). A DDST was performed to screen for synergy between antibiotic combinations., Results: Using MH-AV, all SBL- and MBL-positive Enterobacterales were susceptible or susceptible at increased exposure to the combination AT-avibactam. In contrast, only 2 out of the 12 (17%) P. aeruginosa strains and 9/11 (82%) of the S. maltophilia strains were susceptible- or susceptible at increased exposure for the combination of AT-avibactam. The DDST detected all synergies, demonstrating a 100% sensitivity and 100% negative predictive value for all bacterial strains., Conclusion: The DDST is a sensitive tool for screening for antibiotic synergy. Unlike S. maltophilia and SBL- and MBL-positive Enterobacterales , most MBL-positive P. aeruginosa strains remain resistant to AT-avibactam. ATA GDS should be preferred for MIC determination of the AT-avibactam combination, while the GDSs superposition method can be used as an alternative to the commercial test., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Verschelden, Noeparast, Stoefs, Van Honacker, Vandoorslaer, Vandervore, Olbrecht, Van Damme, Demuyser, Piérard and Wybo.) more...
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- 2023
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6. False positive Herpes Simplex IgM serology in COVID-19 patients correlates with SARS-CoV-2 IgM/IgG seropositivity.
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Vandervore L, Van Mieghem E, Nowé V, Schouwers S, Steger C, Abrams P, Van Schaeren J, Meskal A, and Vandamme T
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- Antibodies, Viral, Humans, Immunoassay methods, Immunoglobulin G, Immunoglobulin M, SARS-CoV-2, Sensitivity and Specificity, COVID-19 diagnosis, Herpes Simplex diagnosis, Pneumonia, Viral diagnosis
- Abstract
Differentiating COVID-19 from other causes of viral pneumonia, like herpes simplex (HSV), can be complicated by shared clinical and laboratory features. Viral pneumonia is mostly diagnosed based on molecular or serological techniques. Serological immunoassay interferences, often attributed to concurrent appearance of heterologous (viral) immunoglobulins, is well-known, but has not been studied in COVID-19 patients. Following false positive HSV immunoglobulin M (IgM) results in our index patient, 25 other COVID-19 patients were tested for HSV-1/2 IgM with the chemiluminescent Liaison assay and Euroimmun enzyme-linked immunosorbent assay. Forty-five percent of COVID-19 patients tested positive for HSV IgM with Liaison. No HSV indices were positive with Euroimmun enzyme-linked immunosorbent assay, suggesting immunoassay interference. Significant correlation between HSV IgM and SARS-CoV-2 IgM/IgG positivity was found. Adding 0.5% polyvinylpyrrolidone, inhibiting non-specific solid-phase adsorption, abolished interference in 22% of false positive cases, suggesting interference caused by solid-phase reactive IgM. Hence, serologic immunoassay results should be interpreted with caution in COVID-19 patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.) more...
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- 2022
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7. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
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Magini P, Smits DJ, Vandervore L, Schot R, Columbaro M, Kasteleijn E, van der Ent M, Palombo F, Lequin MH, Dremmen M, de Wit MCY, Severino M, Divizia MT, Striano P, Ordonez-Herrera N, Alhashem A, Al Fares A, Al Ghamdi M, Rolfs A, Bauer P, Demmers J, Verheijen FW, Wilke M, van Slegtenhorst M, van der Spek PJ, Seri M, Jansen AC, Stottmann RW, Hufnagel RB, Hopkin RJ, Aljeaid D, Wiszniewski W, Gawlinski P, Laure-Kamionowska M, Alkuraya FS, Akleh H, Stanley V, Musaev D, Gleeson JG, Zaki MS, Brunetti-Pierri N, Cappuccio G, Davidov B, Basel-Salmon L, Bazak L, Shahar NR, Bertoli-Avella A, Mirzaa GM, Dobyns WB, Pippucci T, Fornerod M, and Mancini GMS more...
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- Arthrogryposis pathology, Cell Lineage, Child, Endoplasmic Reticulum metabolism, Female, Gene Expression Profiling, HEK293 Cells, Humans, Male, Microcephaly pathology, Mitosis, Neurodevelopmental Disorders pathology, Pedigree, RNA Splicing, Arthrogryposis genetics, Microcephaly genetics, Neurodevelopmental Disorders genetics, Sphingomyelin Phosphodiesterase genetics
- 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., (Copyright © 2019 American Society of Human Genetics. All rights reserved.) more...
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- 2019
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8. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.
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Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, Dremmen MHG, Schot R, Vandervore L, van Slegtenhorst MA, Wilke M, Kasteleijn E, Lee AS, Barry BJ, Chao KR, Szczałuba K, Kobori J, Hanson-Kahn A, Bernstein JA, Carr L, D'Arco F, Miyana K, Okazaki T, Saito Y, Sasaki M, Das S, Wheeler MM, Bamshad MJ, Nickerson DA, Engle EC, Verheijen FW, Doherty D, and Mancini GMS more...
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- Adolescent, Brain Stem pathology, Child, Child, Preschool, Cilia genetics, Female, Humans, Lissencephaly genetics, Male, Microtubules genetics, Nervous System Malformations genetics, Axon Guidance genetics, Cell Movement genetics, Conserved Sequence genetics, Microfilament Proteins genetics, Mutation genetics, Neurons pathology, Zinc metabolism
- Abstract
To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2018
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9. Biallelic mutations in RTTN are associated with microcephaly, short stature and a wide range of brain malformations.
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Stouffs K, Moortgat S, Vanderhasselt T, Vandervore L, Dica A, Mathot M, Keymolen K, Seneca S, Gheldof A, De Meirleir L, and Jansen AC
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- Adolescent, Adult, Agenesis of Corpus Callosum genetics, Agenesis of Corpus Callosum pathology, Brain Diseases pathology, Cell Cycle Proteins, Cerebral Cortex pathology, Child, Child, Preschool, Corpus Callosum pathology, Developmental Disabilities genetics, Developmental Disabilities pathology, Dwarfism pathology, Female, Humans, Infant, Lateral Ventricles pathology, Male, Microcephaly pathology, Nervous System Malformations genetics, Nervous System Malformations pathology, Young Adult, Brain Diseases genetics, Carrier Proteins genetics, Dwarfism genetics, Lateral Ventricles abnormalities, Microcephaly genetics
- Abstract
Biallelic mutations in the RTTN gene have been reported in association with microcephaly, short stature, developmental delay and malformations of cortical development. RTTN mutations have previously shown to link aberrant ciliary function with abnormal development and organization of the human cerebral cortex. We here report three individuals from two unrelated families with novel mutations in the RTTN gene. The phenotype consisted of microcephaly, short stature, pachygyria or polymicrogyria, colpocephaly, hypoplasia of the corpus callosum and superior vermis. These findings provide further confirmation of the phenotype related to pathogenic variants in RTTN., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.) more...
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- 2018
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10. Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts.
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Vandervore L, Stouffs K, Tanyalçin I, Vanderhasselt T, Roelens F, Holder-Espinasse M, Jørgensen A, Pepin MG, Petit F, Khau Van Kien P, Bahi-Buisson N, Lissens W, Gheldof A, Byers PH, and Jansen AC
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- Adult, Alleles, Cells, Cultured, Cerebellar Diseases genetics, Cerebellar Diseases pathology, Child, Child, Preschool, Cysts pathology, Exome genetics, Exons genetics, Female, Fibroblasts pathology, Humans, Ligands, Magnetic Resonance Imaging methods, Male, Malformations of Cortical Development pathology, Mutation genetics, Phenotype, Young Adult, Collagen Type III genetics, Cysts genetics, Malformations of Cortical Development genetics, Receptors, G-Protein-Coupled genetics, White Matter pathology
- Abstract
Background: Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded by COL3A1 , is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations in GPR56 give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations in COL3A1 are associated with a similar phenotype., Methods: Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations in COL3A1 were reviewed. Functional assays were performed on dermal fibroblasts., Results: Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1 . Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic COL3A1 mutations showed a brain phenotype similar to that associated with mutations in GPR56 ., Conclusion: Homozygous or compound heterozygous mutations in COL3A1 are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic COL3A1 mutations emphasises the critical role of the type III collagen-GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.) more...
- Published
- 2017
- Full Text
- View/download PDF
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