43 results on '"Mitter D"'
Search Results
2. Mikrodeletionssyndrom 9q34 – ein charakteristischer Phänotyp
- Author
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Mitter, D., Buiting, K., and Gillessen-Kaesbach, G.
- Published
- 2007
- Full Text
- View/download PDF
3. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy
- Author
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Johannesen, Km, Mitter, D, Janowski, R, Roth, C, Toulouse, J, Poulat, Al, Ville, Dm, Chatron, N, Brilstra, E, Geleijns, K, Born, Ap, McLean, S, Nugent, K, Baynam, G, Poulton, C, Dreyer, L, Gration, D, Schulz, S, Dieckmann, A, Helbig, Kl, Merkenschlager, A, Jamra, R, Finck, A, Gardella, E, Hjalgrim, H, Mirzaa, G, Brancati, F, Bierhals, T, Denecke, J, Hempel, M, Lemke, Jr, Rubboli, G, Muschke, P, Guerrini, R, Vetro, A, Niessing, D, Lesca, G, and Møller, Rs
- Subjects
TRANSFER-RNA-SYNTHETASE ,ILAE COMMISSION ,POSITION PAPER ,MUTATIONS ,CLASSIFICATION ,DEFICIENCY ,FEATURES - Published
- 2020
4. Germline AGO2 mutations impair RNA interference and human neurological development
- Author
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Lessel, D., Zeitler, D.M., Reijnders, M.R.F., Kazantsev, A., Nia, F. Hassani, Bartholomäus, A., Martens, V., Bruckmann, A., Graus, V., McConkie-Rosell, A., McDonald, M., Lozic, B., Tan, E.S., Gerkes, E., Johannsen, J., Denecke, J., Telegrafi, A., Zonneveld-Huijssoon, E., Lemmink, H.H., Cham, B.W.M., Kovacevic, T., Ramsdell, L., Foss, K., Duc, D. Le, Mitter, D., Syrbe, S., Merkenschlager, A., Sinnema, M., Panis, B., Lazier, J., Osmond, M., Hartley, T., Mortreux, J., Busa, T., Missirian, C., Prasun, P., Lüttgen, S., Mannucci, I., Lessel, I., Schob, C., Kindler, S., Pappas, J., Rabin, R., Willemsen, M.H., Gardeitchik, T., Löhner, K., Rump, P., Dias, K.R., Evans, C.A., Andrews, P.I., Roscioli, T., Brunner, H.G., Chijiwa, C., Lewis, M.E.S., Jamra, R.A., Dyment, D.A., Boycott, K.M., Stegmann, A.P.A., Kubisch, C., Tan, Ene-Choo, Mirzaa, G.M., McWalter, K., Kleefstra, T., Pfundt, R.P., Ignatova, Z., Meister, G., Kreienkamp, H.J., Lessel, D., Zeitler, D.M., Reijnders, M.R.F., Kazantsev, A., Nia, F. Hassani, Bartholomäus, A., Martens, V., Bruckmann, A., Graus, V., McConkie-Rosell, A., McDonald, M., Lozic, B., Tan, E.S., Gerkes, E., Johannsen, J., Denecke, J., Telegrafi, A., Zonneveld-Huijssoon, E., Lemmink, H.H., Cham, B.W.M., Kovacevic, T., Ramsdell, L., Foss, K., Duc, D. Le, Mitter, D., Syrbe, S., Merkenschlager, A., Sinnema, M., Panis, B., Lazier, J., Osmond, M., Hartley, T., Mortreux, J., Busa, T., Missirian, C., Prasun, P., Lüttgen, S., Mannucci, I., Lessel, I., Schob, C., Kindler, S., Pappas, J., Rabin, R., Willemsen, M.H., Gardeitchik, T., Löhner, K., Rump, P., Dias, K.R., Evans, C.A., Andrews, P.I., Roscioli, T., Brunner, H.G., Chijiwa, C., Lewis, M.E.S., Jamra, R.A., Dyment, D.A., Boycott, K.M., Stegmann, A.P.A., Kubisch, C., Tan, Ene-Choo, Mirzaa, G.M., McWalter, K., Kleefstra, T., Pfundt, R.P., Ignatova, Z., Meister, G., and Kreienkamp, H.J.
- Abstract
Contains fulltext : 229431.pdf (publisher's version ) (Open Access), ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
- Published
- 2020
5. Molecular and clinical studies in 8 patients with Temple syndrome
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Gillessen‐Kaesbach, G., primary, Albrecht, B., additional, Eggermann, T., additional, Elbracht, M., additional, Mitter, D., additional, Morlot, S., additional, van Ravenswaaij‐Arts, C.M.A., additional, Schulz, S., additional, Strobl‐Wildemann, G., additional, Buiting, K., additional, and Beygo, J., additional
- Published
- 2018
- Full Text
- View/download PDF
6. FOXG1 Syndrome: Genotype–Phenotype Association in 84 Patients with FOXG1 Variants
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Mitter, D., additional, Pringsheim, M., additional, Kaulisch, M., additional, Plümacher, K., additional, Schröder, S., additional, Warthemann, R., additional, Malzahn, D., additional, Zirn, B., additional, and Brockmann, K., additional
- Published
- 2017
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7. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes
- Author
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Kratz, C P, primary, Franke, L, additional, Peters, H, additional, Kohlschmidt, N, additional, Kazmierczak, B, additional, Finckh, U, additional, Bier, A, additional, Eichhorn, B, additional, Blank, C, additional, Kraus, C, additional, Kohlhase, J, additional, Pauli, S, additional, Wildhardt, G, additional, Kutsche, K, additional, Auber, B, additional, Christmann, A, additional, Bachmann, N, additional, Mitter, D, additional, Cremer, F W, additional, Mayer, K, additional, Daumer-Haas, C, additional, Nevinny-Stickel-Hinzpeter, C, additional, Oeffner, F, additional, Schlüter, G, additional, Gencik, M, additional, Überlacker, B, additional, Lissewski, C, additional, Schanze, I, additional, Greene, M H, additional, Spix, C, additional, and Zenker, M, additional
- Published
- 2015
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8. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss
- Author
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Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, Millán JM, Aller E, Mitter D, and Bolz H
- Subjects
otorhinolaryngologic diseases - Abstract
Usher syndrome is an autosomal recessive condition characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP). The seven proteins that have been identified for Usher syndrome type 1 (USH1) and type 2 (USH2) may interact in a large protein complex. In order to identify novel USH genes, we followed a candidate strategy, assuming that mutations in proteins interacting with this "USH network" may cause Usher syndrome as well. The DFNB31 gene encodes whirlin, a PDZ scaffold protein with expression in both hair cell stereocilia and retinal photoreceptor cells. Whirlin represents an excellent candidate for USH2 because it binds to Usherin (USH2A) and VLGR1b (USH2C). Genotyping of microsatellite markers specific for the DFNB31 gene locus on chromosome 9q32 was performed in a German USH2 family that had been excluded for all known USH loci. Patients showed common haplotypes. Sequence analysis of DFNB31 revealed compound heterozygosity for a nonsense mutation, p.Q103X, in exon 1, and a mutation in the splice donor site of exon 2, c.837+1G>A. DFNB31 mutations appear to be a rare cause of Usher syndrome, since no mutations were identified in an additional 96 USH2 patients. While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function. We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. Moreover, this is the first case of USH2 that is allelic to non-syndromic deafness.
- Published
- 2007
9. Identification of novel estrogen receptor beta splice variants in MDA-MB-231 breast cancer cells
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Treeck, O, Federhofer, B, Houlihan, H, Vollmer, A, Mitter, D, Pfeiler, G, Horn, F, and Ortmann, O
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ddc: 610 - Published
- 2006
10. Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin
- Author
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Ghani-Kakhki, M., primary, Robinson, P.N., additional, Morlot, S., additional, Mitter, D., additional, Trimborn, M., additional, Albrecht, B., additional, Varon, R., additional, Sperling, K., additional, and Neitzel, H., additional
- Published
- 2012
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11. MOTA Syndrome: Molecular Genetic Confirmation of the Diagnosis in a Newborn with Previously Unreported Clinical Features
- Author
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Mitter, D., primary, Schanze, D., additional, Sterker, I., additional, Müller, D., additional, Till, H., additional, and Zenker, M., additional
- Published
- 2012
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12. Östrogenrezeptor-β-Isoformen -Funktionen und klinische Bedeutung bei Brustkrebs
- Author
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Mitter, D., primary, Ortmann, O., additional, and Treeck, O., additional
- Published
- 2005
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13. The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content.
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Mitter, D., Reisinger, C., Hinz, B., Hollmann, S., Yelamanchili, S.V., Treiber-Held, S., Ohm, T.G., Herrmann, A., and Ahnert-Hilger, G.
- Subjects
- *
MEMBRANE proteins , *SYNAPSES - Abstract
Synaptophysin interacts with synaptobrevin in membranes of adult small synaptic vesicles. The synaptophysin/synaptobrevin complex promotes synaptobrevin to built up functional SNARE complexes thereby modulating synaptic efficiency. Synaptophysin in addition is a cholesterol-binding protein. Depleting the membranous cholesterol content by filipin or β-methylcyclodextrin (β-MCD) decreased the solubility of synaptophysin in Triton X-100 with less effects on synaptobrevin. In small synaptic vesicles from rat brain the synaptophysin/synaptobrevin complex was diminished upon β-MCD treatment as revealed by chemical cross-linking. Mice with a genetic mutation in the Niemann–Pick C1 gene developing a defect in cholesterol sorting showed significantly reduced amounts of the synaptophysin/synaptobrevin complex compared to their homo- or heterozygous littermates. Finally when using primary cultures of mouse hippocampus the synaptophysin/synaptobrevin complex was down-regulated after depleting the endogenous cholesterol content by the HMG-CoA-reductase inhibitor lovastatin. Alternatively, treatment with cholesterol up-regulated the synaptophysin/synaptobrevin interaction in these cultures. These data indicate that the synaptophysin/synaptobrevin interaction critically depends on a high cholesterol content in the membrane of synaptic vesicles. Variations in the availability of cholesterol may promote or impair synaptic efficiency by interfering with this complex. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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14. Defining QARS: Catastrophic Epilepsy, Microcephaly And Encephalopathy
- Author
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Johannesen, Katrine M., Toulouse, J., Mitter, D., L Poulat, A., Ville, D., Brilstra, E., Geleijns, K. P., Born, A. P., Elena Gardella, Rubboli, G., Lesca, G., Lemke, J., and Rikke S. Møller
15. Germline AGO2 mutations impair RNA interference and human neurological development.
- Author
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Lessel D, Zeitler DM, Reijnders MRF, Kazantsev A, Hassani Nia F, Bartholomäus A, Martens V, Bruckmann A, Graus V, McConkie-Rosell A, McDonald M, Lozic B, Tan ES, Gerkes E, Johannsen J, Denecke J, Telegrafi A, Zonneveld-Huijssoon E, Lemmink HH, Cham BWM, Kovacevic T, Ramsdell L, Foss K, Le Duc D, Mitter D, Syrbe S, Merkenschlager A, Sinnema M, Panis B, Lazier J, Osmond M, Hartley T, Mortreux J, Busa T, Missirian C, Prasun P, Lüttgen S, Mannucci I, Lessel I, Schob C, Kindler S, Pappas J, Rabin R, Willemsen M, Gardeitchik T, Löhner K, Rump P, Dias KR, Evans CA, Andrews PI, Roscioli T, Brunner HG, Chijiwa C, Lewis MES, Jamra RA, Dyment DA, Boycott KM, Stegmann APA, Kubisch C, Tan EC, Mirzaa GM, McWalter K, Kleefstra T, Pfundt R, Ignatova Z, Meister G, and Kreienkamp HJ
- Subjects
- Adolescent, Animals, Argonaute Proteins chemistry, Child, Child, Preschool, Cluster Analysis, Dendrites metabolism, Fibroblasts metabolism, Gene Silencing, HEK293 Cells, Hippocampus pathology, Humans, Mice, Molecular Dynamics Simulation, Neurons metabolism, Phosphorylation, Protein Domains, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering metabolism, RNA-Induced Silencing Complex metabolism, Rats, Transcriptome genetics, Argonaute Proteins genetics, Germ Cells metabolism, Mutation genetics, Nervous System growth & development, Nervous System metabolism, RNA Interference
- Abstract
ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
- Published
- 2020
- Full Text
- View/download PDF
16. Defining and expanding the phenotype of QARS -associated developmental epileptic encephalopathy.
- Author
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Johannesen KM, Mitter D, Janowski R, Roth C, Toulouse J, Poulat AL, Ville DM, Chatron N, Brilstra E, Geleijns K, Born AP, McLean S, Nugent K, Baynam G, Poulton C, Dreyer L, Gration D, Schulz S, Dieckmann A, Helbig KL, Merkenschlager A, Jamra R, Finck A, Gardella E, Hjalgrim H, Mirzaa G, Brancati F, Bierhals T, Denecke J, Hempel M, Lemke JR, Rubboli G, Muschke P, Guerrini R, Vetro A, Niessing D, Lesca G, and Møller RS
- Abstract
Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy., Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding., Results: Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype., Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2019
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17. PEDIA: prioritization of exome data by image analysis.
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Hsieh TC, Mensah MA, Pantel JT, Aguilar D, Bar O, Bayat A, Becerra-Solano L, Bentzen HB, Biskup S, Borisov O, Braaten O, Ciaccio C, Coutelier M, Cremer K, Danyel M, Daschkey S, Eden HD, Devriendt K, Wilson S, Douzgou S, Đukić D, Ehmke N, Fauth C, Fischer-Zirnsak B, Fleischer N, Gabriel H, Graul-Neumann L, Gripp KW, Gurovich Y, Gusina A, Haddad N, Hajjir N, Hanani Y, Hertzberg J, Hoertnagel K, Howell J, Ivanovski I, Kaindl A, Kamphans T, Kamphausen S, Karimov C, Kathom H, Keryan A, Knaus A, Köhler S, Kornak U, Lavrov A, Leitheiser M, Lyon GJ, Mangold E, Reina PM, Carrascal AM, Mitter D, Herrador LM, Nadav G, Nöthen M, Orrico A, Ott CE, Park K, Peterlin B, Pölsler L, Raas-Rothschild A, Randolph L, Revencu N, Fagerberg CR, Robinson PN, Rosnev S, Rudnik S, Rudolf G, Schatz U, Schossig A, Schubach M, Shanoon O, Sheridan E, Smirin-Yosef P, Spielmann M, Suk EK, Sznajer Y, Thiel CT, Thiel G, Verloes A, Vrecar I, Wahl D, Weber I, Winter K, Wiśniewska M, Wollnik B, Yeung MW, Zhao M, Zhu N, Zschocke J, Mundlos S, Horn D, and Krawitz PM
- Subjects
- Algorithms, Databases, Genetic, Deep Learning, Exome genetics, Female, Genomics, Humans, Male, Phenotype, Software, Computational Biology methods, Image Processing, Computer-Assisted methods, Sequence Analysis, DNA methods
- Abstract
Purpose: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists., Methods: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds., Results: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene., Conclusion: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.
- Published
- 2019
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18. Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4.
- Author
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Ballin N, Hotz A, Bourrat E, Küsel J, Oji V, Bouadjar B, Brognoli D, Hickman G, Heinz L, Vabres P, Marrakchi S, Leclerc-Mercier S, Irvine A, Tadini G, Hamm H, Has C, Blume-Peytavi U, Mitter D, Reitenbach M, Hausser I, Zimmer AD, Alter S, and Fischer J
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- Adult, Aged, Aged, 80 and over, Biopsy, Cell Line, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Pedigree, Receptors, Cell Surface chemistry, Sequence Analysis, DNA, Young Adult, Ichthyosis genetics, Ichthyosis pathology, Mutation, Receptors, Cell Surface genetics
- Abstract
Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)
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- 2019
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19. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.
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Renner S, Schüler H, Alawi M, Kolbe V, Rybczynski M, Woitschach R, Sheikhzadeh S, Stark VC, Olfe J, Roser E, Seggewies FS, Mahlmann A, Hempel M, Hartmann MJ, Hillebrand M, Wieczorek D, Volk AE, Kloth K, Koch-Hogrebe M, Abou Jamra R, Mitter D, Altmüller J, Wey-Fabrizius A, Petersen C, Rau I, Borck G, Kubisch C, Mir TS, von Kodolitsch Y, Kutsche K, and Rosenberger G
- Subjects
- Adult, Aorta metabolism, Biomarkers metabolism, Cohort Studies, Connective Tissue metabolism, Connective Tissue pathology, Connective Tissue Diseases physiopathology, Female, Genetic Testing, Humans, Male, Marfan Syndrome diagnosis, Marfan Syndrome physiopathology, Aorta physiopathology, Connective Tissue Diseases genetics, High-Throughput Nucleotide Sequencing, Marfan Syndrome genetics
- Abstract
Purpose: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management., Methods: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity., Results: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants., Conclusion: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.
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- 2019
- Full Text
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20. Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.
- Author
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Pringsheim M, Mitter D, Schröder S, Warthemann R, Plümacher K, Kluger G, Baethmann M, Bast T, Braun S, Büttel HM, Conover E, Courage C, Datta AN, Eger A, Grebe TA, Hasse-Wittmer A, Heruth M, Höft K, Kaindl AM, Karch S, Kautzky T, Korenke GC, Kruse B, Lutz RE, Omran H, Patzer S, Philippi H, Ramsey K, Rating T, Rieß A, Schimmel M, Westman R, Zech FM, Zirn B, Ulmke PA, Sokpor G, Tuoc T, Leha A, Staudt M, and Brockmann K
- Subjects
- Animals, Child Development Disorders, Pervasive genetics, Child Development Disorders, Pervasive pathology, Female, Genotype, Humans, Intellectual Disability genetics, Mice, Transgenic, Microcephaly genetics, Phenotype, Rett Syndrome genetics, Brain abnormalities, Brain pathology, Forkhead Transcription Factors genetics, Nerve Tissue Proteins genetics
- Abstract
Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations., Methods: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1 +/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies., Results: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix., Interpretation: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome., Competing Interests: Nothing to report.
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- 2019
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21. [Disseminated linear and irregular pigmentation of the skin].
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Haiduk J, Brockstedt LA, Mitter D, Hiemisch A, Merkenschlager A, Simon JC, and Kunz M
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- Humans, Skin, Pigmentation Disorders, Skin Pigmentation
- Published
- 2018
- Full Text
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22. Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development.
- Author
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Platzer K, Cogné B, Hague J, Marcelis CL, Mitter D, Oberndorff K, Park SM, Ploos van Amstel HK, Simonic I, van der Smagt JJ, Stegmann APA, Stevens SJC, Stumpel CTRM, Vincent M, Lemke JR, and Jamra R
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- Adult, Child, Child, Preschool, Female, Genetic Variation genetics, Humans, Male, Transcription Factors, Developmental Disabilities diagnosis, Developmental Disabilities genetics, Haploinsufficiency genetics, Homeodomain Proteins genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Nuclear Proteins genetics, Repressor Proteins genetics
- Abstract
Objective: Developmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology., Methods: We clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER., Results: All 9 individuals harbored heterozygous null-allele variants in CUX1, encoding the Cut-homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age-related intelligence at ages 4, 6, and 8 years after a previous history of significant DD., Interpretation: Our results suggest that null-allele variants, and thus haploinsufficiency of CUX1, cause an isolated phenotype of DD or ID with possible catch-up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200-207., (© 2018 American Neurological Association.)
- Published
- 2018
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23. FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.
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Mitter D, Pringsheim M, Kaulisch M, Plümacher KS, Schröder S, Warthemann R, Abou Jamra R, Baethmann M, Bast T, Büttel HM, Cohen JS, Conover E, Courage C, Eger A, Fatemi A, Grebe TA, Hauser NS, Heinritz W, Helbig KL, Heruth M, Huhle D, Höft K, Karch S, Kluger G, Korenke GC, Lemke JR, Lutz RE, Patzer S, Prehl I, Hoertnagel K, Ramsey K, Rating T, Rieß A, Rohena L, Schimmel M, Westman R, Zech FM, Zoll B, Malzahn D, Zirn B, and Brockmann K
- Subjects
- Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Phenotype, Polymorphism, Single Nucleotide, Forkhead Transcription Factors genetics, Genetic Association Studies, Genetic Variation, Nerve Tissue Proteins genetics, Rett Syndrome diagnosis, Rett Syndrome genetics
- Abstract
PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.
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- 2018
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24. Biallelic COL3A1 mutations result in a clinical spectrum of specific structural brain anomalies and connective tissue abnormalities.
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Horn D, Siebert E, Seidel U, Rost I, Mayer K, Abou Jamra R, Mitter D, and Kornak U
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- Brain abnormalities, Brain diagnostic imaging, Brain physiopathology, Child, Preschool, Codon, Nonsense, Connective Tissue diagnostic imaging, Connective Tissue physiopathology, Developmental Disabilities diagnostic imaging, Developmental Disabilities physiopathology, Ehlers-Danlos Syndrome diagnostic imaging, Ehlers-Danlos Syndrome physiopathology, Female, Heterozygote, Humans, Male, Malformations of Cortical Development diagnostic imaging, Malformations of Cortical Development physiopathology, Mutation, Missense, Pedigree, Phenotype, Receptors, G-Protein-Coupled genetics, Collagen Type III genetics, Developmental Disabilities genetics, Ehlers-Danlos Syndrome genetics, Malformations of Cortical Development genetics
- Abstract
Vascular Ehlers-Danlos syndrome (type IV) is an autosomal dominant disorder caused by heterozygous variants of COL3A1. We identified biallelic COL3A1 variants in two unrelated families. In a 3-year-old female with developmental delay the nonsense variant c.1282C>T, p.(Arg428*) was detected in combination the c.2057delC, p.(Pro686Leufs*105) frame shift variant. Both compound heterozygous variants were novel. This patient was born with bilateral clubfoot, joint laxity, and dysmorphic facial features. At the age of 2 years she developed an aneurysmal brain hemorrhage. Cerebral MRI showed a peculiar pattern of profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C
- Published
- 2017
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25. Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome.
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Neuhaus C, Eisenberger T, Decker C, Nagl S, Blank C, Pfister M, Kennerknecht I, Müller-Hofstede C, Charbel Issa P, Heller R, Beck B, Rüther K, Mitter D, Rohrschneider K, Steinhauer U, Korbmacher HM, Huhle D, Elsayed SM, Taha HM, Baig SM, Stöhr H, Preising M, Markus S, Moeller F, Lorenz B, Nagel-Wolfrum K, Khan AO, and Bolz HJ
- Abstract
Background: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP)., Methods: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome., Results: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3 , genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome., Conclusion: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.
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- 2017
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26. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.
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Kouz K, Lissewski C, Spranger S, Mitter D, Riess A, Lopez-Gonzalez V, Lüttgen S, Aydin H, von Deimling F, Evers C, Hahn A, Hempel M, Issa U, Kahlert AK, Lieb A, Villavicencio-Lorini P, Ballesta-Martinez MJ, Nampoothiri S, Ovens-Raeder A, Puchmajerová A, Satanovskij R, Seidel H, Unkelbach S, Zabel B, Kutsche K, and Zenker M
- Subjects
- Cardiomyopathy, Hypertrophic pathology, Female, Genetic Association Studies, Genotype, Germ-Line Mutation, Heart Defects, Congenital pathology, Humans, Male, Noonan Syndrome pathology, Pedigree, Phenotype, Cardiomyopathy, Hypertrophic genetics, Heart Defects, Congenital genetics, Noonan Syndrome genetics, ras Proteins genetics
- Abstract
Purpose: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited., Methods: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed., Results: Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent., Conclusion: RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.
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- 2016
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27. Identification of a Novel Point Mutation in the LEMD3 Gene in an Infant With Buschke-Ollendorff Syndrome.
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Kratzsch J, Mitter D, Ziemer M, Kohlhase J, and Voth H
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- Biopsy, Needle, DNA-Binding Proteins, Genetic Predisposition to Disease, Humans, Immunohistochemistry, Infant, Prognosis, Rare Diseases, Severity of Illness Index, Membrane Proteins genetics, Nuclear Proteins genetics, Osteopoikilosis genetics, Osteopoikilosis pathology, Point Mutation, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology
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- 2016
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28. Late onset dHMN II caused by c.404C>G mutation in HSPB1 gene.
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Oberstadt M, Mitter D, Classen J, and Baum P
- Abstract
Distal hereditary motor neuropathy (dHMN) type II is genetically heterogeneous. We report three siblings of a German family with late onset distal motor neuropathy due to the c.404C>G mutation in heat-shock 27-kDa protein 1 gene (HSPB1/HSP27). A 36-year-old mutation carrier, daughter of one sibling, did not present any clinical or electrophysiological abnormalities. The index patient (oldest brother) developed weakness of the distal lower limbs and nocturnal muscle cramps at the age of 54. After 5 years this patient developed an l-DOPA-responsive hypokinetic rigid syndrome, establishing a diagnosis of Parkinson's disease. Although none of the three other mutation carriers displayed Parkinsonian signs, a pathogenic relationship with Parkinson's disease remains a possibility, based on the known molecular pathology of HSPB1. The rare pathogenic HSPB1 c.404C>G mutation may predispose for late-onset of dHMN type II., (© 2016 Peripheral Nerve Society.)
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- 2016
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29. A 33-year-old male patient with paternal derived duplication of 14q11.2-14q22.1~22.3: clinical course, phenotypic and genotypic findings.
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Wannenmacher B, Mitter D, Kießling F, Liehr T, Weise A, Siekmeyer M, and Kiess W
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- Abnormalities, Multiple pathology, Adult, Child, Chromosomes, Human, Pair 14 genetics, Female, Genotype, Humans, In Situ Hybridization, Fluorescence, Intellectual Disability pathology, Male, Mosaicism, Phenotype, Prognosis, Young Adult, Abnormalities, Multiple genetics, Chromosomes, Human, Pair 6 genetics, Gene Duplication genetics, Intellectual Disability genetics, Trisomy genetics
- Abstract
We report on a 33-year-old patient with mosaic interstitial duplication on chromosome 14q11.2-14q22.1~22.3 with severe physical and mental retardation and multiple dysmorphisms. This patient was admitted to our pediatric hospital due to severe dehydration and malnutrition as a result of food refusal. It is an actual phenomenon that patients with severe inborn clinical problems nowadays survive due to progress and care of modern medicine. Nevertheless, transition from pediatric care to adult medicine seems to remain a challenging problem. We demonstrate the clinical course as well as clinical and genetic findings of this adult patient. Comparisons are made to previously reported cases with mosaic trisomy 14 involving a proximal interstitial duplication on the long arm of chromosome 14.
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- 2016
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30. Novel peroxisome proliferator-activated receptor gamma mutation in a family with familial partial lipodystrophy type 3.
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Miehle K, Porrmann J, Mitter D, Stumvoll M, Glaser C, Fasshauer M, and Hoffmann K
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- Adult, Base Sequence, Crystallography, X-Ray, DNA Mutational Analysis methods, Family Health, Female, Heterozygote, Humans, Male, Middle Aged, Models, Molecular, PPAR gamma chemistry, Pedigree, Protein Conformation, Genetic Predisposition to Disease genetics, Lipodystrophy, Familial Partial genetics, Mutation, Missense, PPAR gamma genetics
- Abstract
Objective: Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder with loss of subcutaneous adipose tissue at the extremities and metabolic complications such as insulin resistance, hypertriglyceridaemia and hypertension. The aim of this study was to characterize the molecular basis of a family of 5 affected members with FPLD3., Methods: A 61-year-old female index patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequence analysis of the LMNA and PPARG gene was performed. Structure analysis of the identified mutation was carried out using published X-ray crystal structures., Results: A novel heterozygous PPARG mutation c.1040A>C was identified in all 5 patients of the family but not in unaffected controls. The resulting amino acid substitution p.Lys347Thr is located at the ligand-binding domain (LBD) of the protein and is predicted to disrupt critical molecular interactions to the helix 12 of the LBD., Conclusions: A novel PPARG mutation leading to FPLD3 is described. The results emphasize the importance of the clinical diagnosis and of further molecular genetic analyses in patients with clinical signs of FPLD but unremarkable LMNA findings., (© 2015 John Wiley & Sons Ltd.)
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- 2016
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31. Duplication Xp11.22-p14 in females: does X-inactivation help in assessing their significance?
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Evers C, Mitter D, Strobl-Wildemann G, Haug U, Hackmann K, Maas B, Janssen JW, Jauch A, Hinderhofer K, and Moog U
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- Adolescent, Adult, Child, Child, Preschool, Comparative Genomic Hybridization, Facies, Female, Genetic Association Studies, Humans, Phenotype, Polymorphism, Single Nucleotide, Sex Chromosome Disorders diagnosis, Young Adult, Chromosome Duplication, Chromosomes, Human, X, Sex Chromosome Disorders genetics, X Chromosome Inactivation
- Abstract
In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic., (© 2015 Wiley Periodicals, Inc.)
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- 2015
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32. A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring.
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Rump A, Hildebrand L, Tzschach A, Ullmann R, Schrock E, and Mitter D
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- Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 9 genetics, DNA Mutational Analysis, Exons genetics, Family Health, Female, Humans, Introns genetics, Male, RNA Splicing, RNA, Messenger genetics, RNA, Messenger metabolism, Transcription, Genetic, Young Adult, Craniofacial Abnormalities genetics, Heart Defects, Congenital genetics, Histone-Lysine N-Methyltransferase genetics, Intellectual Disability genetics, Point Mutation, RNA Splice Sites genetics
- Abstract
The euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene was examined in a 3-year-old boy with characteristic clinical features of Kleefstra syndrome. Sequencing of all 27 EHMT1 exons revealed a novel mutation, NM_024757.4:c.2712+1G>A, which affects the splice donor of intron 18. Whereas the index patient is heterozygous for that mutation, his phenotypically normal mother shows tissue-specific mosaicism. Sequencing of EHMT1 RT-PCR products revealed two aberrant transcript variants: in one variant, exon 18 was skipped; in the other, a near-by GT motif was used as splice donor and intronic sequence was inserted between exons 18 and 19. Both transcript variants were found in the patient and his mother. The latter had lower amounts of these transcripts consistent with mosaic status. This is the first description of an EHMT1 point mutation being inherited from a parent with verified mosaicism. The constitutive c.2712+1G>A splice site mutation in EHMT1 is fully pathogenic, and the transcript variants produced do not attenuate the severity of the disease.
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- 2013
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33. Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C.
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Starke S, Meinke P, Camozzi D, Mattioli E, Pfaeffle R, Siekmeyer M, Hirsch W, Horn LC, Paasch U, Mitter D, Lattanzi G, Wehnert M, and Kiess W
- Subjects
- DNA Repair, Fatal Outcome, Female, Humans, Infant, Lamin Type A genetics, Mutation, Pedigree, Cockayne Syndrome genetics, Cockayne Syndrome pathology, Lamin Type A metabolism, Skin Abnormalities genetics, Skin Abnormalities pathology
- Abstract
The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.
- Published
- 2013
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34. Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions.
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Mitter D, Ullmann R, Muradyan A, Klein-Hitpass L, Kanber D, Ounap K, Kaulisch M, and Lohmann D
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- Abnormalities, Multiple genetics, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 13 genetics, Female, Humans, Infant, Infant, Newborn, Male, Microcephaly genetics, Chromosome Disorders genetics, Genes, Retinoblastoma genetics, Genetic Association Studies, Retinoblastoma genetics
- Abstract
Patients with an interstitial 13q deletion that contains the RB1 gene show retinoblastoma and variable clinical features. Relationship between phenotypic expression and loss of specific neighboring genes are unresolved, yet. We obtained clinical, cytogenetic and molecular data in 63 patients with an interstitial 13q deletion involving RB1. Whole-genome array analysis or customized high-resolution array analysis for 13q14.11q14.3 was performed in 38 patients, and cytogenetic analysis was performed in 54 patients. Deletion sizes ranged between 4.2 kb and more than 33.43 Mb; breakpoints were non-recurrent. Sequence analysis of deletion junctions in five patients revealed microhomology and insertion of 2-34 base pairs suggestive of non-homologous end joining. Milder phenotypic expression of retinoblastoma was observed in patients with deletions larger than 1 Mb, which contained the MED4 gene. Clinical features were compared between patients with small (within 13q14), medium (within 13q12.3q21.2) and large (within 13q12q31.2) deletions. Patients with a small deletion can show macrocephaly, tall stature, obesity, motor and/or speech delay. Patients with a medium deletion show characteristic facial features, mild to moderate psychomotor delay, short stature and microcephaly. Patients with a large deletion have characteristic craniofacial dysmorphism, short stature, microcephaly, mild to severe psychomotor delay, hypotonia, constipation and feeding problems. Additional features included deafness, seizures and brain and heart anomalies. We found no correlation between clinical features and parental origin of the deletion. Our data suggest that hemizygous loss of NUFIP1 and PCDH8 may contribute to psychomotor delay, deletion of MTLR1 to microcephaly and loss of EDNRB to feeding difficulties and deafness.
- Published
- 2011
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35. Genotype-phenotype correlation in eight new patients with a deletion encompassing 2q31.1.
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Mitter D, Chiaie BD, Lüdecke HJ, Gillessen-Kaesbach G, Bohring A, Kohlhase J, Caliebe A, Siebert R, Roepke A, Ramos-Arroyo MA, Nieva B, Menten B, Loeys B, Mortier G, and Wieczorek D
- Subjects
- Adult, Child, Child, Preschool, Chromosome Breakage, Comparative Genomic Hybridization, Female, Foot Deformities, Congenital complications, Foot Deformities, Congenital diagnostic imaging, Foot Deformities, Congenital genetics, Hand Deformities, Congenital complications, Hand Deformities, Congenital diagnostic imaging, Hand Deformities, Congenital genetics, Humans, Infant, Infant, Newborn, Karyotyping, Male, Pregnancy, Radiography, Chromosome Deletion, Chromosomes, Human, Pair 2 genetics, Genetic Association Studies
- Abstract
Microdeletions of the 2q31.1 region are rare. We present the clinical and molecular findings of eight previously unreported patients with overlapping deletions in 2q31.1. The patients have a variable clinical phenotype and present with developmental delay (7/8), growth retardation (5/8), seizures (2/8) and a craniofacial dysmorphism consisting of microcephaly (4/8), short palpebral fissures (7/8), broad eyebrows with lateral flare (7/8), low-set ears with thickened helices and lobules (5/8), and micrognathia (6/8). Additional congenital anomalies were noted, including limb abnormalities (8/8), heart defects (3/8), genital anomalies (3/8), and craniosynostosis (1/8). Six of these microdeletions, ranging in size from 1.24 to 8.35 Mb, were identified by array CGH, one larger deletion (19.7 Mb) was detected by conventional karyotyping and further characterized by array CGH analysis. The smallest region of overlap in all eight patients spans at most 88 kb and includes only the WIPF1 gene. This gene codes for the WAS/WASL interacting protein family member 1. The patients described here do not present with clinical signs of the Wiskott-Aldrich syndrome and the deletion of this single gene does not allow explaining the phenotype in our patients. It is likely that the deletion of different but overlapping sets of genes from 2q31 is responsible for the clinical variability in these patients. To further dissect the complex phenotype associated with deletions in 2q31, additional patients with overlapping phenotypes should be examined with array CGH. This should help to link particular phenotypes to specific genes, and add to our understanding of the underlying developmental processes., (Copyright 2010 Wiley-Liss, Inc.)
- Published
- 2010
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36. The human retinoblastoma gene is imprinted.
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Kanber D, Berulava T, Ammerpohl O, Mitter D, Richter J, Siebert R, Horsthemke B, Lohmann D, and Buiting K
- Subjects
- Allelic Imbalance drug effects, Allelic Imbalance genetics, Animals, Azacitidine pharmacology, CpG Islands genetics, Gene Expression Profiling, Gene Expression Regulation drug effects, Genetic Loci genetics, Genomic Imprinting drug effects, Humans, Lymphocytes drug effects, Lymphocytes metabolism, Macaca mulatta genetics, Pan troglodytes genetics, Pseudogenes genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Genomic Imprinting genetics, Retinoblastoma Protein genetics
- Abstract
Genomic imprinting is an epigenetic process leading to parent-of-origin-specific DNA methylation and gene expression. To date, approximately 60 imprinted human genes are known. Based on genome-wide methylation analysis of a patient with multiple imprinting defects, we have identified a differentially methylated CpG island in intron 2 of the retinoblastoma (RB1) gene on chromosome 13. The CpG island is part of a 5'-truncated, processed pseudogene derived from the KIAA0649 gene on chromosome 9 and corresponds to two small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In four other KIAA0649 pseudogene copies, which are located on chromosome 22, the two CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analysing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2'-deoxycytidine-treated lymphoblastoid cells, we have found that differential methylation of the CpG island skews RB1 gene expression in favor of the maternal allele. Thus, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2009
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37. Identification of a mutation in exon 27 of the RB1 gene associated with incomplete penetrance retinoblastoma.
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Mitter D, Rushlow D, Nowak I, Ansperger-Rescher B, Gallie BL, and Lohmann DR
- Subjects
- Amino Acid Sequence, Base Sequence, Exons genetics, Humans, Male, Molecular Sequence Data, Mutation, Pedigree, Reverse Transcriptase Polymerase Chain Reaction, Genes, Retinoblastoma genetics, Genetic Predisposition to Disease, Penetrance, Retinal Neoplasms genetics, Retinoblastoma genetics, Retinoblastoma Protein genetics
- Abstract
Retinoblastoma (Rb) is initiated by germline mutations in the RB1 gene. Up to date, no mutation was identified in exons 26 and 27. We have identified a 2 bp frameshift insertion in exon 27 of the RB1 gene (RBg.177008_177009dup) in a boy with unilateral Rb and his healthy father that has occurred de novo on the allele transmitted by the father's father. RT-PCR showed that the mutant +2 bp transcript is present in RNA from peripheral leukocytes after short-term culture. The level of the mutant transcript was low compared to the normal transcript indicating abnormal expression of the variant allele. The mutant transcript was further reduced after puromycin treatment suggesting that NMD is not involved. Although oncogenic mutations in the terminal exons of the RB1 gene are rare molecular testing is important as those terminal mutations can be associated with incomplete penetrance and cause high recurrence risk in family members.
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- 2009
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38. Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father.
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Mitter D, Krakow D, Farrington-Rock C, and Meinecke P
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- Adult, Bone and Bones abnormalities, Child, Contractile Proteins genetics, Filamins, Growth Disorders etiology, Humans, Inheritance Patterns, Male, Microfilament Proteins genetics, Phenotype, Syndrome, Fathers, Growth Disorders genetics, Heterozygote, Spine abnormalities, Synostosis complications, Synostosis genetics
- Abstract
We report on a 5-year-old boy with spondylocarpotarsal synostosis (SCT) syndrome who presents with disproportionate short stature, thoracic scoliosis, pes planus, dental enamel hypoplasia, unilateral conductive hearing loss and mild facial dysmorphisms. Radiographs showed abnormal segmentation of the spine with block vertebrae and carpal synostosis. In addition to the typical phenotype of SCT syndrome, he showed pronounced delay of carpal bone age and bilateral epiphyseal dysplasia of the proximal femora. The patient's father has mild short stature and unilateral hip dysplasia. Molecular studies of the filamin B gene (FLNB) revealed a homozygous mutation in the index patient while both parents were heterozygous for the mutation. In this report we expand the phenotype of SCT syndrome in a patient with a causal FLNB mutation., ((c) 2008 Wiley-Liss, Inc.)
- Published
- 2008
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39. Estrogen receptor {beta}1 exerts antitumoral effects on SK-OV-3 ovarian cancer cells.
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Treeck O, Pfeiler G, Mitter D, Lattrich C, Piendl G, and Ortmann O
- Subjects
- Alternative Splicing, Apoptosis, Blotting, Western methods, Cell Line, Tumor, Cell Movement, Cell Proliferation, Estrogen Receptor beta genetics, Exons, Female, Humans, Protein Isoforms genetics, RNA Interference, RNA, Small Interfering pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Transfection methods, Wound Healing, Estrogen Receptor beta metabolism, Gene Expression Regulation, Neoplastic, Ovarian Neoplasms metabolism, Protein Isoforms metabolism
- Abstract
Estrogen receptor (ER) beta1 and its splice variants are expressed both in ovary and ovarian cancer. We studied the role of ERbeta1 and two of its splice variants in regulation of gene expression, cellular proliferation, apoptosis, and migration of an ovarian cancer cell line. In this study, we transfected SK-OV-3 ovarian cancer cells with vectors coding for ERbeta1 or its splice variants ERbeta-delta125 and ERbeta-delta1256, and tested their response to estrogen and tamoxifen in comparison with the untransfected cells. Heterologous expression of ERbeta1, but not of the exon-deleted ERbeta variants resulted in notably slower cell growth of SK-OV-3 ovarian cancer cells, an effect accompanied by more than tenfold increase of cyclin-dependent kinase inhibitor p21(WAF1) transcript levels and a significant reduction of cyclin A2 mRNA levels. SK-OV-3 cells stably overexpressing ERbeta1 ligand independently also exhibited an increased apoptosis rate and a significantly decreased motility, an effect accompanied by upregulation of fibulin 1c. Our data demonstrate that ERbeta1, but not the exon-deleted isoforms tested exerts multiple antitumoral effects on SK-OV-3 ovarian cancer cells even in the absence of estradiol or functional ERalpha.
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- 2007
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40. Is there a higher incidence of maternal uniparental disomy 14 [upd(14)mat]? Detection of 10 new patients by methylation-specific PCR.
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Mitter D, Buiting K, von Eggeling F, Kuechler A, Liehr T, Mau-Holzmann UA, Prott EC, Wieczorek D, and Gillessen-Kaesbach G
- Subjects
- Adolescent, Child, Child, Preschool, Cytogenetics, DNA Methylation, Female, Humans, Infant, Infant, Low Birth Weight, Infant, Newborn, Male, Microsatellite Repeats, Obesity genetics, Phenotype, Polymerase Chain Reaction, Prader-Willi Syndrome genetics, Pregnancy, Proteins genetics, RNA, Long Noncoding, Translocation, Genetic, Chromosomes, Human, Pair 14 genetics, Uniparental Disomy
- Abstract
Maternal uniparental disomy for chromosome 14 [upd(14)mat] is associated with a characteristic phenotype including pre- and postnatal growth retardation, muscular hypotonia, feeding problems, motor delay, small hands and feet, precocious puberty and truncal obesity. Patients with upd(14)mat show features overlapping with Prader-Willi syndrome (PWS) and are probably underdiagnosed. Maternal upd(14) is frequently described in carriers of a Robertsonian translocation involving chromosome 14, but is also found in patients with a normal karyotype. Based on the above mentioned criteria we have identified six patients with upd(14)mat including two patients with a normal karyotype, one patient with a de novo Robertsonian translocation (14;21), one patient with a familial Robertsonian translocation (13;14) and two patients with a marker chromosome. In addition, we analyzed a cohort of 33 patients with low birth weight, feeding difficulties and consecutive obesity in whom PWS had been excluded by methylation analysis of SNRPN. In four of these patients (12%) we detected upd(14)mat. For rapid testing of upd(14)mat we analyzed the methylation status of the imprinted MEG3 locus. In conclusion, we recommend considering upd(14)mat in patients with low birth weight, growth retardation, neonatal feeding problems, muscular hypotonia, motor delay, precocious puberty and truncal obesity as well as in patients with a PWS like phenotype presenting with low birth weight, feeding difficulties and obesity.
- Published
- 2006
- Full Text
- View/download PDF
41. [Estrogen receptor Beta isoforms -- functions and clinical relevance in breast cancer].
- Author
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Mitter D, Ortmann O, and Treeck O
- Subjects
- Breast Neoplasms pathology, Estrogen Receptor alpha physiology, Female, Humans, Protein Isoforms physiology, Treatment Outcome, Breast Neoplasms physiopathology, Breast Neoplasms therapy, Estrogen Receptor beta physiology
- Abstract
Estrogen receptors (ER) are hormone regulated transcription factors which mediate the cellular estrogen response. So far two types of ER could be identified, ERalpha and ERbeta. ERalpha plays an important role as a predictive factor for the effectiveness of endocrine agents in the treatment of breast cancer. Patients with ERalpha positive tumors receive adjuvant endocrine therapy. Recent findings indicate a crucial role of ERbeta and its isoforms for the prognosis of breast cancer. This paper reviews the current knowledge on the functions of ERbeta and its splice variants.
- Published
- 2005
- Full Text
- View/download PDF
42. The synaptophysin/synaptobrevin complex dissociates independently of neuroexocytosis.
- Author
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Reisinger C, Yelamanchili SV, Hinz B, Mitter D, Becher A, Bigalke H, and Ahnert-Hilger G
- Subjects
- Animals, Botulinum Toxins, Type A pharmacology, Brain Chemistry, Calcium metabolism, Cells, Cultured, Dimerization, Exocytosis drug effects, Hippocampus cytology, Ionophores pharmacology, Macromolecular Substances, Magnesium pharmacology, Membrane Proteins chemistry, Membrane Proteins drug effects, Mice, Nerve Tissue Proteins drug effects, Nerve Tissue Proteins metabolism, Neurons cytology, Neurons drug effects, Protein Binding drug effects, R-SNARE Proteins, Rats, Spider Venoms pharmacology, Stimulation, Chemical, Synaptophysin chemistry, Synaptosomal-Associated Protein 25, Synaptosomes chemistry, Synaptosomes drug effects, Tetanus Toxin chemistry, Tetanus Toxin pharmacology, Exocytosis physiology, Membrane Proteins metabolism, Neurons metabolism, Synaptophysin metabolism
- Abstract
Synaptophysin is one of the most abundant membrane proteins of small synaptic vesicles. In mature nerve terminals it forms a complex with the vesicular membrane protein synaptobrevin, which appears to modulate synaptobrevin's interaction with the plasma membrane-associated proteins syntaxin and SNAP25 to form the SNARE complex as a prerequisite for membrane fusion. Here we show that synaptobrevin is preferentially cleaved by tetanus toxin while bound to synaptophysin or when existing as a homodimer. The synaptophysin/synaptobrevin complex is, however, not affected when neuronal secretion is blocked by botulinum A toxin which cleaves SNAP25. Excessive stimulation with alpha-latrotoxin or Ca(2+)-ionophores dissociates the synaptophysin/synaptobrevin complex and increases the interaction of the other SNARE proteins. The stimulation-induced dissociation of the synaptophysin/synaptobrevin complex is not inhibited by pre-incubating neurones with botulinum A toxin, but depends on extracellular calcium. However, the synaptophysin/synaptobrevin complex cannot be directly dissociated by calcium alone or in combination with magnesium. The dissociation of synaptobrevin from synaptophysin appears to precede its interaction with the other SNARE proteins and does not depend on the final fusion event. This finding further supports the modulatory role the synaptophysin/synaptobrevin complex may play in mature neurones.
- Published
- 2004
- Full Text
- View/download PDF
43. Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain.
- Author
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Hinz B, Becher A, Mitter D, Schulze K, Heinemann U, Draguhn A, and Ahnert-Hilger G
- Subjects
- Age Factors, Amygdala physiopathology, Animals, Epilepsy physiopathology, Kindling, Neurologic physiology, Nerve Tissue Proteins metabolism, Neuronal Plasticity physiology, Qa-SNARE Proteins, R-SNARE Proteins, Rats, SNARE Proteins, Synaptosomal-Associated Protein 25, Amygdala metabolism, Epilepsy metabolism, Membrane Proteins metabolism, Presynaptic Terminals metabolism, Synaptophysin metabolism, Vesicular Transport Proteins
- Abstract
The vesicular protein synaptobrevin contributes to two mutually exclusive complexes in mature synapses. Synaptobrevin tightly interacts with the plasma membrane proteins syntaxin and SNAP 25 forming the SNARE complex as a prerequisite for exocytotic membrane fusion. Alternatively, synaptobrevin binds to the vesicular protein synaptophysin. It is unclear whether SNARE complex formation is diminished or facilitated when synaptobrevin is bound to synaptophysin. Here we show that the synaptophysin-synaptobrevin complex is increased in adult rat brain after repeated synaptic hyperactivity in the kindling model of epilepsy. Two days after the last kindling-induced stage V seizure the relative amount of synaptophysin-synaptobrevin complex obtained by co-immunoprecipitation from cortical and hippocampal membranes was increased twofold compared to controls. By contrast the relative amounts of various synaptic proteins as well as that of the SNARE complex did not change in membrane preparations from kindled rats compared to controls. The increased amount of synaptophysin-synaptobrevin complex in kindled rats supports the idea that this complex represents a reserve pool for synaptobrevin enabling synaptic vesicles to adjust to an increased demand for synaptic efficiency. We conclude that the synaptophysin-synaptobrevin interaction is involved in activity-dependent plastic changes in adult rat brain.
- Published
- 2001
- Full Text
- View/download PDF
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