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21 results on '"Kaya, Sabine"'

1. Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions

Author

Mohren, Lars, Erdlenbruch, Friedrich, Leitão, Elsa, Kilpert, Fabian, Hönes, G. Sebastian, Kaya, Sabine, Schröder, Christopher, Thieme, Andreas, Sturm, Marc, Park, Joohyun, Schlüter, Agatha, Ruiz, Montserrat, Morales de la Prida, Moisés, Casasnovas, Carlos, Becker, Kerstin, Roggenbuck, Ulla, Pechlivanis, Sonali, Kaiser, Frank J., Synofzik, Matthis, Wirth, Thomas, Anheim, Mathieu, Haack, Tobias B., Lockhart, Paul J., Jöckel, Karl-Heinz, Pujol, Aurora, Klebe, Stephan, Timmann, Dagmar, and Depienne, Christel

Published
2024
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2. Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling

Author

Schuermans, Nika, El Chehadeh, Salima, Hemelsoet, Dimitri, Gautheron, Jérémie, Vantyghem, Marie-Christine, Nouioua, Sonia, Tazir, Meriem, Vigouroux, Corinne, Auclair, Martine, Bogaert, Elke, Dufour, Sara, Okawa, Fumiya, Hilbert, Pascale, Van Doninck, Nike, Taquet, Marie-Caroline, Rosseel, Toon, De Clercq, Griet, Debackere, Elke, Van Haverbeke, Carole, Cherif, Ferroudja Ramdane, Urtizberea, Jon Andoni, Chanson, Jean-Baptiste, Funalot, Benoit, Authier, François-Jérôme, Kaya, Sabine, Terryn, Wim, Callens, Steven, Depypere, Bernard, Van Dorpe, Jo, Poppe, Bruce, Impens, Francis, Mizushima, Noboru, Depienne, Christel, Jéru, Isabelle, and Dermaut, Bart

Published
2023
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3. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Author

Leitão, Elsa, Schröder, Christopher, Parenti, Ilaria, Dalle, Carine, Rastetter, Agnès, Kühnel, Theresa, Kuechler, Alma, Kaya, Sabine, Gérard, Bénédicte, Schaefer, Elise, Nava, Caroline, Drouot, Nathalie, Engel, Camille, Piard, Juliette, Duban-Bedu, Bénédicte, Villard, Laurent, Stegmann, Alexander PA, Vanhoutte, Els K, Verdonschot, Job AJ, Kaiser, Frank J, Tran Mau-Them, Frédéric, Scala, Marcello, Striano, Pasquale, Frints, Suzanna GM, Argilli, Emanuela, Sherr, Elliott H, Elder, Fikret, Buratti, Julien, Keren, Boris, Mignot, Cyril, Héron, Delphine, Mandel, Jean-Louis, Gecz, Jozef, Kalscheuer, Vera M, Horsthemke, Bernhard, Piton, Amélie, and Depienne, Christel

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Biotechnology, Autism, Human Genome, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Mental health, Humans, Chromosomes, Human, X, Genes, X-Linked, Intellectual Disability, Autism Spectrum Disorder, Databases, Genetic
Abstract

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

Published
2022

4. An intragenic duplication in the AFF2 gene associated with Cornelia de Lange syndrome phenotype.

Author

Lucia-Campos, Cristina, Parenti, Ilaria, Latorre-Pellicer, Ana, Gil-Salvador, Marta, Bestetti, Ilaria, Finelli, Palma, Larizza, Lidia, Arnedo, María, Ayerza-Casas, Ariadna, Del Rincón, Julia, Trujillano, Laura, Morte, Beatriz, Pérez-Jurado, Luis A., Lapunzina, Pablo, Leitão, Elsa, Beygo, Jasmin, Lich, Christina, Kilpert, Fabian, Kaya, Sabine, and Depienne, Christel

Subjects
COMPARATIVE genomic hybridization, DIZYGOTIC twins, MOLECULAR diagnosis, GENE expression, CONGENITAL disorders
Abstract

Cornelia de Lange syndrome (CdLS, OMIM #122470, #300590, #300882, #610759, and #614701) is a rare congenital disorder that affects the development of multiple organs and is characterized by physical abnormalities and cognitive and behavioral disabilities. Its molecular basis is mainly based on alterations in genes encoding structural and regulatory proteins related to the cohesin complex. Moreover, other transcriptional regulatory factors have been linked to this syndrome. However, additional causative genes are still unknown, since many patients still lack a molecular diagnosis. Herein, we describe a case with multiple affected family members presenting with an intragenic duplication in the AFF2 gene. The direct tandem intragenic duplication of exons 10, 11 and 12 was detected through high-resolution array Comparative Genomic Hybridization and next-generation sequencing technologies. Confirming the X-linked inheritance pattern, the duplication was found in the patient, his mother and his maternal aunt affected (dizygotic twins). Targeted sequencing with Oxford Nanopore Technologies revealed an aberrant transcript which is predominantly expressed in the patient and his aunt. Along with these results, a significant reduction in AFF2 gene expression levels was detected in these two individuals. Clinically both subjects exhibit a classic CdLS phenotype, whereas the mother is mostly unaffected. Consistent with the phenotypical differences observed between the mother and the aunt, there is a marked difference in X-inactivation patterns skewing. Given the crucial role of AFF2 in transcriptional regulation, it is not surprising that AFF2 variants can give rise to CdLS phenotypes. Therefore, the AFF2 gene should be considered for the molecular diagnosis of this syndrome. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Unveiling pathogenic and non-pathogenic FGF14 repeat expansions: identification, sequence, and secondary structure

Author

Depienne, Christel, primary, Mohren, Lars, additional, Erdlenbruch, Friedrich, additional, Leitão, Elsa, additional, Kilpert, Fabian, additional, Hönes, G. Sebastian, additional, Thieme, Andreas, additional, Sturm, Marc, additional, Park, Joohyun, additional, Schlüter, Agatha, additional, Ruiz, Montserrat, additional, Prida, Moisés Morales de la, additional, Casasnovas, Carlos, additional, Becker, Kerstin, additional, Roggenbuck, Ulla, additional, Pechlivanis, Sonali, additional, Kaiser, Frank, additional, Synofzik, Matthis, additional, Wirth, Thomas, additional, Anheim, Mathieu, additional, Haack, Tobias, additional, Lockhart, Paul, additional, Jöckel, Karl-Heinz, additional, Pujol, Aurora, additional, Klebe, Stephan, additional, Timmann, Dagmar, additional, Kaya, Sabine, additional, and Schroeder, Christopher, additional

Published
2024
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6. Advancing molecular, phenotypic and mechanistic insights ofFGF14pathogenic expansions (SCA27B)

Author

Mohren, Lars, primary, Erdlenbruch, Friedrich, additional, Leitão, Elsa, additional, Kilpert, Fabian, additional, Hönes, G. Sebastian, additional, Kaya, Sabine, additional, Schröder, Christopher, additional, Thieme, Andreas, additional, Sturm, Marc, additional, Park, Joohyun, additional, Schlüter, Agatha, additional, Ruiz, Montserrat, additional, Morales de la Prida, Moisés, additional, Casasnovas, Carlos, additional, Becker, Kerstin, additional, Roggenbuck, Ulla, additional, Pechlivanis, Sonali, additional, Kaiser, Frank J., additional, Synofzik, Matthis, additional, Wirth, Thomas, additional, Anheim, Mathieu, additional, Haack, Tobias B., additional, Lockhart, Paul J., additional, Jöckel, Karl-Heinz, additional, Pujol, Aurora, additional, Klebe, Stephan, additional, Timmann, Dagmar, additional, and Depienne, Christel, additional

Published
2024
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9. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Author

Corbett, Mark A., Kroes, Thessa, Veneziano, Liana, Bennett, Mark F., Florian, Rahel, Schneider, Amy L., Coppola, Antonietta, Licchetta, Laura, Franceschetti, Silvana, Suppa, Antonio, Wenger, Aaron, Mei, Davide, Pendziwiat, Manuela, Kaya, Sabine, Delledonne, Massimo, Straussberg, Rachel, Xumerle, Luciano, Regan, Brigid, Crompton, Douglas, van Rootselaar, Anne-Fleur, Correll, Anthony, Catford, Rachael, Bisulli, Francesca, Chakraborty, Shreyasee, Baldassari, Sara, Tinuper, Paolo, Barton, Kirston, Carswell, Shaun, Smith, Martin, Berardelli, Alfredo, Carroll, Renee, Gardner, Alison, Friend, Kathryn L., Blatt, Ilan, Iacomino, Michele, Di Bonaventura, Carlo, Striano, Salvatore, Buratti, Julien, Keren, Boris, Nava, Caroline, Forlani, Sylvie, Rudolf, Gabrielle, Hirsch, Edouard, Leguern, Eric, Labauge, Pierre, Balestrini, Simona, Sander, Josemir W., Afawi, Zaid, Helbig, Ingo, Ishiura, Hiroyuki, Tsuji, Shoji, Sisodiya, Sanjay M., Casari, Giorgio, Sadleir, Lynette G., van Coller, Riaan, Tijssen, Marina A. J., Klein, Karl Martin, van den Maagdenberg, Arn M. J. M., Zara, Federico, Guerrini, Renzo, Berkovic, Samuel F., Pippucci, Tommaso, Canafoglia, Laura, Bahlo, Melanie, Striano, Pasquale, Scheffer, Ingrid E., Brancati, Francesco, Depienne, Christel, and Gecz, Jozef

Published
2019
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11. Familial Cerebellar Ataxia and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia withDAB1andC9ORF72Repeat Expansions: An 18‐Year Study

Author

Rosenbohm, Angela, primary, Pott, Hendrik, additional, Thomsen, Mirja, additional, Rafehi, Haloom, additional, Kaya, Sabine, additional, Szymczak, Silke, additional, Volk, Alexander E., additional, Mueller, Kathrin, additional, Silveira, Isabel, additional, Weishaupt, Jochen H., additional, Tönnies, Holger, additional, Seibler, Philip, additional, Zschiedrich, Katja, additional, Schaake, Susen, additional, Westenberger, Ana, additional, Zühlke, Christine, additional, Depienne, Christel, additional, Trinh, Joanne, additional, Ludolph, Albert C., additional, Klein, Christine, additional, Bahlo, Melanie, additional, and Lohmann, Katja, additional

Published
2022
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12. Familial Cerebellar Ataxia and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia with DAB1 and C9ORF72 Repeat Expansions: An 18-Year Study

Author

Rosenbohm, Angela, Pott, Hendrik, Tönnies, Holger, Seibler, Philip, Zschiedrich, Katja, Schaake, Susen, Westenberger, Ana, Zühlke, Christine, Depienne, Christel, Trinh, Joanne, Ludolph, Albert C, Klein, Christine, Thomsen, Mirja, Bahlo, Melanie, Lohmann, Katja, Rafehi, Haloom, Kaya, Sabine, Szymczak, Silke, Volk, Alexander E, Mueller, Kathrin, Silveira, Isabel, and Weishaupt, Jochen H

Subjects
genetics [Cerebellar Ataxia], DAB1, repeat expansion, genetics [DNA Repeat Expansion], Medizin, diagnostic imaging [Frontotemporal Dementia], frontotemporal dementia, genome sequencing, genetics [Amyotrophic Lateral Sclerosis], spinocerebellar ataxia, SCA37, diagnostic imaging [Amyotrophic Lateral Sclerosis], genetics [Adaptor Proteins, Signal Transducing], nanopore sequencing, linkage studies in genetics, Humans, ddc:610, genetics [Spinocerebellar Ataxias], ALS, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], genetics [Nerve Tissue Proteins]
Abstract

Background: Coding and noncoding repeat expansions are an important cause of neurodegenerative diseases. Objective: This study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co-occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short-read genome sequencing, long-read sequencing, repeat-primed polymerase chain reaction, and Southern blotting. Results: The family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1-related ataxia (ATX-DAB1; SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT]≈₇₅[ATTTC]≈₄₀₋₁₀₀[ATTTT]≈₄₁₅). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection. Conclusion: We demonstrate genetic and clinical findings during an 18-year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022
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13. Systematic analysis and prediction of genes associated with disorders on chromosome X

Author

Leitão, Elsa, primary, Schröder, Christopher, additional, Parenti, Ilaria, additional, Dalle, Carine, additional, Rastetter, Agnès, additional, Kühnel, Theresa, additional, Kuechler, Alma, additional, Kaya, Sabine, additional, Gérard, Bénédicte, additional, Schaefer, Elise, additional, Nava, Caroline, additional, Drouot, Nathalie, additional, Engel, Camille, additional, Piard, Juliette, additional, Duban-Bedu, Bénédicte, additional, Villard, Laurent, additional, Stegmann, Alexander P.A., additional, Vanhoutte, Els K., additional, Verdonshot, Job A.J, additional, Kaiser, Frank J., additional, Mau-Them, Frédéric Tran, additional, Scala, Marcello, additional, Striano, Pasquale, additional, Frints, Suzanna G.M., additional, Argilli, Emanuela, additional, Sherr, Elliott H., additional, Elder, Fikret, additional, Buratti, Julien, additional, Keren, Boris, additional, Mignot, Cyril, additional, Héron, Delphine, additional, Mandel, Jean-Louis, additional, Gecz, Jozef, additional, Kalscheuer, Vera M., additional, Horsthemke, Bernhard, additional, Piton, Amélie, additional, and Depienne, Christel, additional

Published
2022
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14. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian, Rahel T., Kraft, Florian, Leitão, Elsa, Kaya, Sabine, Klebe, Stephan, Magnin, Eloi, van Rootselaar, Anne-Fleur, Buratti, Julien, Kühnel, Theresa, Schröder, Christopher, Giesselmann, Sebastian, Tschernoster, Nikolai, Altmueller, Janine, Lamiral, Anaide, Keren, Boris, Nava, Caroline, Bouteiller, Delphine, Forlani, Sylvie, Jornea, Ludmila, Kubica, Regina, Ye, Tao, Plassard, Damien, Jost, Bernard, Meyer, Vincent, Deleuze, Jean-François, Delpu, Yannick, Avarello, Mario D. M., Vijfhuizen, Lisanne S., Rudolf, Gabrielle, Hirsch, Edouard, Kroes, Thessa, Reif, Philipp S., Rosenow, Felix, Ganos, Christos, Vidailhet, Marie, Thivard, Lionel, Mathieu, Alexandre, Bourgeron, Thomas, Kurth, Ingo, Rafehi, Haloom, Steenpaß, Laura, Horsthemke, Bernhard, LeGuern, Eric, Klein, Karl Martin, Labauge, Pierre, Bennett, Mark F., Bahlo, Melanie, Gecz, Jozef, Corbett, Mark A., Tijssen, Marina A. J., van den Maagdenberg, Arn M. J. M., and Depienne, Christel

Subjects
Medizinische Fakultät » Universitätsklinikum Essen » Institut für Humangenetik, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Neurologie, ddc:610
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Published
2019

15. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian, Rahel T, Kraft, Florian, Leitão, Elsa, Kaya, Sabine, Klebe, Stephan, Magnin, Eloi, van Rootselaar, Anne-Fleur, Buratti, Julien, Kühnel, Theresa, Schröder, Christopher, Giesselmann, Sebastian, Tschernoster, Nikolai, Altmueller, Janine, Lamiral, Anaide, Keren, Boris, Nava, Caroline, Bouteiller, Delphine, Forlani, Sylvie, Jornea, Ludmila, Kubica, Regina, Ye, Tao, Plassard, Damien, Jost, Bernard, Meyer, Vincent, Deleuze, Jean-François, Delpu, Yannick, Avarello, Mario D M, Vijfhuizen, Lisanne S, Rudolf, Gabrielle, Hirsch, Edouard, Kroes, Thessa, Reif, Philipp S, Rosenow, Felix, Ganos, Christos, Vidailhet, Marie, Thivard, Lionel, Mathieu, Alexandre, Bourgeron, Thomas, Kurth, Ingo, Rafehi, Haloom, Steenpass, Laura, Horsthemke, Bernhard, LeGuern, Eric, Klein, Karl Martin, Labauge, Pierre, Bennett, Mark F, Bahlo, Melanie, Gecz, Jozef, Corbett, Mark A, Tijssen, Marina A J, and Movement Disorder (MD)

Subjects
GENOME, CORTICAL TREMOR, SEQ, EXCLUSION, LOCUS, LINKAGE, REPEATS, DNA
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Published
2019

17. Disruption of KCNQ1prevents methylation of the ICR2 and supports the hypothesis that its transcription is necessary for imprint establishment

Author

Beygo, Jasmin, Bürger, Joachim, Strom, Tim M., Kaya, Sabine, and Buiting, Karin

Abstract

Beckwith–Wiedemann syndrome (BWS; OMIM #130650) is an imprinting disorder caused by genetic or epigenetic alterations of one or both imprinting control regions on chromosome 11p15.5. Hypomethylation of the centromeric imprinting control region (KCNQ1OT1:TSS-DMR, ICR2) is the most common molecular cause of BWS and is present in about half of the cases. Based on a BWS family with a maternal deletion of the 5’ part of KCNQ1we have recently hypothesised that transcription of KCNQ1is a prerequisite for the establishment of methylation at the KCNQ1OT1:TSS-DMR in the oocyte. Further evidence for this hypothesis came from a mouse model where methylation failed to be established when a poly(A) truncation cassette was inserted into this locus to prevent transcription through the DMR. Here we report on a family where a balanced translocation disrupts the KCNQ1gene in intron 9. Maternal inheritance of this translocation is associated with hypomethylation of the KCNQ1OT1:TSS-DMR and BWS. This finding strongly supports our previous hypothesis that transcription of KCNQ1is required for establishing the maternal methylation imprint at the KCNQ1OT1:TSS-DMR.

Published
2019
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18. The Origin of the RB1 Imprint

Author

Kanber, Deniz, primary, Buiting, Karin, additional, Roos, Christian, additional, Gromoll, Jörg, additional, Kaya, Sabine, additional, Horsthemke, Bernhard, additional, and Lohmann, Dietmar, additional

Published
2013
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19. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian, Rahel T., Kraft, Florian, Leitão, Elsa, Kaya, Sabine, Klebe, Stephan, Magnin, Eloi, Van Rootselaar, Anne-Fleur, Buratti, Julien, Kühnel, Theresa, Schröder, Christopher, Gießelmann, Sebastian, Tschernoster, Nikolai, Altmueller, Janine, Lamiral, Anaide, Keren, Boris, Nava, Caroline, Bouteiller, Delphine, Forlani, Sylvie, Jornea, Ludmila, Kubica, Regina, Ye, Tao, Plassard, Damien, Jost, Bernard, Meyer, Vincent, Deleuze, Jean-François, Delpu, Yannick, Avarello, Mario D. M., Vijfhuizen, Lisanne S., Rudolf, Gabrielle, Hirsch, Edouard, Kroes, Thessa, Reif, Philipp S., Rosenow, Felix, Ganos, Christos, Vidailhet, Marie, Thivard, Lionel, Mathieu, Alexandre, Bourgeron, Thomas, Kurth, Ingo, Rafehi, Haloom, Steenpass, Laura, Horsthemke, Bernhard, LeGuern, Eric, Klein, Karl Martin, Labauge, Pierre, Bennett, Mark F., Bahlo, Melanie, Gecz, Jozef, Corbett, Mark A., Tijssen, Marina A. J., Van Den Maagdenberg, Arn M. J. M., and Depienne, Christel

Subjects
10. No inequality
Abstract

Nature Communications 10, 4919 (2019). doi:10.1038/s41467-019-12763-9, Published by Nature Publishing Group UK, [London]

20. The Origin of the RB1 Imprint.

Author

Kanber, Deniz, Buiting, Karin, Roos, Christian, Gromoll, Jörg, Kaya, Sabine, Horsthemke, Bernhard, and Lohmann, Dietmar

Subjects
RETINOBLASTOMA protein, INTRONS, TUMOR suppressor proteins, TRANSCRIPTION factors, HUMAN genetics, NEW World monkeys
Abstract

The human RB1 gene is imprinted due to a differentially methylated CpG island in intron 2. This CpG island is part of PPP1R26P1, a truncated retrocopy of PPP1R26, and serves as a promoter for an alternative RB1 transcript. We show here by in silico analyses that the parental PPP1R26 gene is present in the analysed members of Haplorrhini, which comprise Catarrhini (Old World Monkeys, Small apes, Great Apes and Human), Platyrrhini (New World Monkeys) and tarsier, and Strepsirrhini (galago). Interestingly, we detected the retrocopy, PPP1R26P1, in all Anthropoidea (Catarrhini and Platyrrhini) that we studied but not in tarsier or galago. Additional retrocopies are present in human and chimpanzee on chromosome 22, but their distinct composition indicates that they are the result of independent retrotransposition events. Chimpanzee and marmoset have further retrocopies on chromosome 8 and chromosome 4, respectively. To examine the origin of the RB1 imprint, we compared the methylation patterns of the parental PPP1R26 gene and its retrocopies in different primates (human, chimpanzee, orangutan, rhesus macaque, marmoset and galago). Methylation analysis by deep bisulfite sequencing showed that PPP1R26 is methylated whereas the retrocopy in RB1 intron 2 is differentially methylated in all primates studied. All other retrocopies are fully methylated, except for the additional retrocopy on marmoset chromosome 4, which is also differentially methylated. Using an informative SNP for the methylation analysis in marmoset, we could show that the differential methylation pattern of the retrocopy on chromosome 4 is allele-specific. We conclude that the epigenetic fate of a PPP1R26 retrocopy after integration depends on the DNA sequence and selective forces at the integration site. [ABSTRACT FROM AUTHOR]

Published
2013
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21. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Author

Florian RT, Kraft F, Leitão E, Kaya S, Klebe S, Magnin E, van Rootselaar AF, Buratti J, Kühnel T, Schröder C, Giesselmann S, Tschernoster N, Altmueller J, Lamiral A, Keren B, Nava C, Bouteiller D, Forlani S, Jornea L, Kubica R, Ye T, Plassard D, Jost B, Meyer V, Deleuze JF, Delpu Y, Avarello MDM, Vijfhuizen LS, Rudolf G, Hirsch E, Kroes T, Reif PS, Rosenow F, Ganos C, Vidailhet M, Thivard L, Mathieu A, Bourgeron T, Kurth I, Rafehi H, Steenpass L, Horsthemke B, LeGuern E, Klein KM, Labauge P, Bennett MF, Bahlo M, Gecz J, Corbett MA, Tijssen MAJ, van den Maagdenberg AMJM, and Depienne C

Subjects
Adolescent, Adult, Aged, Chromosome Mapping, Female, Humans, Introns, Male, Middle Aged, Pedigree, Young Adult, DNA Repeat Expansion, Epilepsies, Myoclonic genetics, Membrane Proteins genetics, Ubiquitin-Protein Ligases genetics
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Published
2019
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