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4. The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc

Author

Ambrozkiewicz, Mateusz C., Borisova, Ekaterina, Schwark, Manuela, Ripamonti, Silvia, Schaub, Theres, Smorodchenko, Alina, Weber, A. Ioana, Rhee, Hong Jun, Altas, Bekir, Yilmaz, Rüstem, Mueller, Susanne, Piepkorn, Lars, Horan, Stephen T., Straussberg, Rachel, Zaqout, Sami, Jahn, Olaf, Dere, Ekrem, Rosário, Marta, Boehm-Sturm, Philipp, Borck, Guntram, Willig, Katrin I., Rhee, JeongSeop, Tarabykin, Victor, and Kawabe, Hiroshi

Published
2021
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5. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice

Author

Spielmann, Malte, Kakar, Naseebullah, Tayebi, Naeimeh, Leettola, Catherine, Nürnberg, Gudrun, Sowada, Nadine, Lupiáñez, Darío G, Harabula, Izabela, Flöttmann, Ricarda, Horn, Denise, Chan, Lee, Wittler, Lars, Yilmaz, Rüstem, Altmüller, Janine, Thiele, Holger, van Bokhoven, Hans, Schwartz, Charles E, Nürnberg, Peter, Bowie, James U, Ahmad, Jamil, Kubisch, Christian, Mundlos, Stefan, and Borck, Guntram

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Congenital Structural Anomalies, Human Genome, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Congenital, Amino Acid Sequence, Animals, Bacterial Proteins, CRISPR-Associated Protein 9, Cell Line, Clustered Regularly Interspaced Short Palindromic Repeats, Coculture Techniques, Endonucleases, Exome, Female, Humans, Limb Deformities, Congenital, Lod Score, MAP Kinase Kinase Kinases, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Site-Directed, Mutation, Missense, Pedigree, Polymorphism, Single Nucleotide, Protein Kinases, Sequence Analysis, DNA, Medical and Health Sciences, Bioinformatics
Abstract

The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in

Published
2016

8. Frequency of C9orf72 and SOD1 mutations in 302 sporadic ALS patients from three German ALS centers

Author

Yilmaz, Rüstem, Grehl, Torsten, Eckrich, Lukas, Marschalkowski, Ines, Weishaupt, Kanchi, Valkadinov, Ivan, Simic, Melita, Brenner, David, Andersen, Peter M., Wolf, Joachim, Weishaupt, Jochen H., Yilmaz, Rüstem, Grehl, Torsten, Eckrich, Lukas, Marschalkowski, Ines, Weishaupt, Kanchi, Valkadinov, Ivan, Simic, Melita, Brenner, David, Andersen, Peter M., Wolf, Joachim, and Weishaupt, Jochen H.

Abstract

Background: ALS patients with a negative family history (sporadic ALS, SALS) represent more than 90% of all ALS cases. In light of the gene-specific therapies that are currently in development for ALS, knowledge about the genetic landscape of SALS in Germany is urgently needed. Objectives: We aimed to determine the frequency of C9orf72 hexanucleotide repeat expansion (HRE) and SOD1 mutations among patients in Germany with a diagnosis of sporadic or idiopathic ALS. Methods: We genotyped SALS patients from three German ALS centers. Sanger sequencing, fragment length analysis, and repeat-primed PCR technologies were used to detect mutations in SOD1 and C9orf72 HRE. Pathological C9orf72 HRE results were confirmed in an independent laboratory. Results: In 302 patients with SALS, 27 (8.9%) patients with a C9orf72 HRE mutation were detected. Moreover, we identified two patients with a pathogenic SOD1 mutation, one patient with a heterozygous p.D91A mutation in SOD1, and three additional patients with rare SOD1 variants not predicted to change the amino acid sequence. Conclusions: According to our data, the proportion of SALS patients with SOD1 mutations is in the expected range, whereas that with C9orf72 HRE is higher, suggesting a reduced penetrance. A considerable number of SALS patients can be amenable to gene-specific therapies.

Published
2023
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10. SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden

Author

Weyen, Ute, Hermann, Andreas, Regensburger, Martin, Winkler, Jürgen, Linker, Ralf, Winner, Beate, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Göricke, Bettina, Zierz, Stephan, Jordan, Berit, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, Kassubek, Jan, Yilmaz, Rüstem, Müller, Kathrin, Brenner, David, Volk, Alexander E., Borck, Guntram, Meitinger, Thomas, Strom, Tim M., Danzer, Karin M., Ludolph, Albert C., Andersen, Peter M., and Weishaupt, Jochen H.

Published
2020
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12. Hot-spot KIF5A mutations cause familial ALS

Author

Brenner, David, Yilmaz, Rüstem, Müller, Kathrin, Grehl, Torsten, Petri, Susanne, Meyer, Thomas, Grosskreutz, Julian, Weydt, Patrick, Ruf, Wolfgang, Neuwirth, Christoph, Weber, Markus, Pinto, Susana, Claeys, Kristl G, Schrank, Berthold, Jordan, Berit, Knehr, Antje, Günther, Kornelia, Hübers, Annemarie, Zeller, Daniel, Kubisch, Christian, Jablonka, Sibylle, Sendtner, Michael, Klopstock, Thomas, de Carvalho, Mamede, Sperfeld, Anne, Borck, Guntram, Volk, Alexander E, Dorst, Johannes, Weis, Joachim, Otto, Markus, Schuster, Joachim, Del Tredici, Kelly, Braak, Heiko, Danzer, Karin M, Freischmidt, Axel, Meitinger, Thomas, Strom, Tim M, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Weyen, Ute, Hermann, Andreas, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Göricke, Bettina, Zierz, Stephan, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, and Kassubek., Jan

Published
2018
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15. Attitudes of Female Students in Secondary Schools Towards Physical Education And Sports (Erzurum Province Sample)

Author

GÜLER, Mehmet Şirin and YILMAZ, Rüstem

Subjects
Beden eğitimi ve spor,kız öğrenciler,tutum, Spor Bilimleri, Physical Education,Sports,Attitude,Female students, Sport Sciences
Abstract

Amaç: Bu araştırma Erzurum ili Yakutiye ilçesinde ortaokulda öğrenim gören kız öğrencilerin beden eğitimi ve spor dersine ilişkin tutumlarını saptamak amacı ile yapılmıştır. Yöntem: Araştırmaya Erzurum Merkez Yakutiye İlçesinde bulunan ortaokullarda 5-6-7 ve 8. sınıflarda öğrenim gören toplam 413 kız öğrenci katılmıştır. Araştırmada Demirhan ve Altay (2001) tarafından geliştirilen, 12’si olumlu 12’si olumsuz olmak üzere toplam 24 maddeden oluşan Beden Eğitimi ve Spor Tutum Ölçeği kullanılmıştır. Ayrıca örneklem grubuna 8 maddelik kişisel bilgi formu uygulanmıştır. Elde edilen veriler; SPSS 24.00 paket programı kullanılarak ortaya çıkarılmıştır. Verilerin analizinde bağımsız örneklem T testi, Levene F Testi sonucuna göre (F= 29,170, p< 0,05) Tek Yönlü Varyans Analizi (Anova) yerine ilişkisiz ölçümler için Kruskal Wallis H Testi yapılmış olup, Kruskal Wallis-H testi sonrası belirlenen anlamlı farklılığın hangi gruplardan kaynaklandığını belirlemek üzere Mann Whitney U Testi yapılmıştır ve bu sonuçlar dikkate alınmıştır. Sonuç: Araştırma sonucunda öğrencilerin beden eğitimi ve spor dersine yönelik olumlu tutum sergiledikleri gözlemlenmiştir. Öğrencilerin beden eğitimi ve spor dersine yönelik tutumlarının; yaş, sınıf düzeyi, okul başarı puanı, spor salonu, anne öğrenim durumu, baba öğrenim durumu, ailede aktif spor yapan birinin olup olmadığı, aile gelir düzeyi değişkenleri açısından anlamlı farklılıklar gösterdiği saptanmıştır (p, Purpose: This research was conducted with the aim of determining the attitudes of female students studying in secondary school in Yakutiye district of Erzurum province towards physical education and sports lessons. Method: A total of 413 female students, 5th grade, 6th grade, 7th and 8th grade, studying at secondary schools in Erzurum Yakutiye District participated in the research. The Physical Education and Sports Attitude Scale, which was developed by Demirhan and Altay (2001), consisting of a total of 24 items, 12 positive and 12 negatives, was used in the study. In addition, an 8-item personal information form was applied to the sample group. The obtained data were analyzed by using the SPSS 24.00 package program. Independent sample T-test and One-Way Analysis of Variance (ANOVA) were used in the analysis of the data. According to the Levene F Test result (F= 29,170, p< 0.05), Kruskal Wallis H Test was used for unrelated measurements instead of One-Way Analysis of Variance (ANOVA), and Mann Whitney U Test was performed to determine which groups caused the significant difference determined after Kruskal Wallis-H test and these results were taken into account. Results and Conclusion: As a conclusion of the research, it was observed that the students exhibited positive attitudes towards physical education and sports lessons. It has been determined that students' attitudes towards physical education and sports lessons show significant differences in terms of age, grade level, school success score, sports hall, their mother's and father's education status, whether there is someone actively doing sports in the family or not, and family income level variables.

Published
2022

17. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

Author

Basel-Vanagaite, Lina, Yilmaz, Rüstem, Tang, Sha, Reuter, Miriam S., Rahner, Nils, Grange, Dorothy K., Mortenson, Megan, Koty, Patrick, Feenstra, Heather, Farwell Gonzalez, Kelly D., Sticht, Heinrich, Boddaert, Nathalie, Désir, Julie, Anyane-Yeboa, Kwame, Zweier, Christiane, Reis, André, Kubisch, Christian, Jewett, Tamison, Zeng, Wenqi, and Borck, Guntram

Published
2014
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22. Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

Author

Mustafa, Rasem, primary, Rawas, Chahinaz, additional, Mannal, Nadja, additional, Kreiner, Grzegorz, additional, Spittau, Björn, additional, Kamińska, Katarzyna, additional, Yilmaz, Rüstem, additional, Pötschke, Christina, additional, Kirsch, Joachim, additional, Liss, Birgit, additional, Tucker, Kerry L., additional, and Parlato, Rosanna, additional

Published
2021
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24. The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc

Author

Ambrozkiewicz, Mateusz C., primary, Borisova, Ekaterina, additional, Schwark, Manuela, additional, Ripamonti, Silvia, additional, Schaub, Theres, additional, Smorodchenko, Alina, additional, Weber, A. Ioana, additional, Rhee, Hong Jun, additional, Altas, Bekir, additional, Yilmaz, Rüstem, additional, Mueller, Susanne, additional, Piepkorn, Lars, additional, Horan, Stephen T., additional, Straussberg, Rachel, additional, Zaqout, Sami, additional, Jahn, Olaf, additional, Dere, Ekrem, additional, Rosário, Marta, additional, Boehm-Sturm, Philipp, additional, Borck, Guntram, additional, Willig, Katrin I., additional, Rhee, JeongSeop, additional, Tarabykin, Victor, additional, and Kawabe, Hiroshi, additional

Published
2020
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25. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

Author

Basel-Vanagaite, Lina, Yilmaz, Rüstem, Tang, Sha, Reuter, Miriam, Rahner, Nils, Grange, Dorothy, Mortenson, Megan, Koty, Patrick, Feenstra, Heather, Farwell Gonzalez, Kelly, Sticht, Heinrich, Boddaert, Nathalie, Désir, Julie, Anyane-Yeboa, Kwame, Zweier, Christiane, Reis, André, Kubisch, Christian, Jewett, Tamison, Zeng, Wenqi, and Borck, Guntram

Abstract

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome”.

Published
2019

26. SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden

Author

Yilmaz, Rüstem, Müller, Kathrin, Brenner, David, Volk, Alexander E., Borck, Guntram, Hermann, Andreas, Meitinger, Thomas, Strom, Tim M., Danzer, Karin M., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Yilmaz, Rüstem, Müller, Kathrin, Brenner, David, Volk, Alexander E., Borck, Guntram, Hermann, Andreas, Meitinger, Thomas, Strom, Tim M., Danzer, Karin M., Ludolph, Albert C., Andersen, Peter M., and Weishaupt, Jochen H.

Abstract

Several studies reported amyotrophic lateral sclerosis (ALS)-linked mutations in TBK1, OPTN, VCP, UBQLN2, and SQSTM1 genes encoding proteins involved in autophagy. SQSTM1 was originally identified by a candidate gene approach because it encodes p62, a multifunctional protein involved in protein degradation both through proteasomal regulation and autophagy. Both p62 and optineurin (encoded by OPTN) are direct interaction partners and substrates of TBK1, and these 3 proteins form the core of a genetic and functional network that may connect autophagy with ALS. Considering the molecular and conceptual relevance of the TBK1/OPTN/SQSTM1 "triangle," we here performed a targeted screen for SQSTM1 variants in 486 patients with familial ALS from Germany and Sweden by analyzing whole-exome sequencing data. We report 9 novel and 5 previously reported rare variants in SQSTM1 and discuss the current evidence for SQSTM1 as a primary disease gene for ALS. We conclude that the evidence for causality remains vague for SQSTM1 and is weaker than for the other autophagy genes, for example, TBK1 and OPTN.

Published
2020
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27. SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden

Author

Yilmaz, Rüstem, primary, Müller, Kathrin, additional, Brenner, David, additional, Volk, Alexander E., additional, Borck, Guntram, additional, Hermann, Andreas, additional, Meitinger, Thomas, additional, Strom, Tim M., additional, Danzer, Karin M., additional, Ludolph, Albert C., additional, Andersen, Peter M., additional, Weishaupt, Jochen H., additional, Weyen, Ute, additional, Regensburger, Martin, additional, Winkler, Jürgen, additional, Linker, Ralf, additional, Winner, Beate, additional, Hagenacker, Tim, additional, Koch, Jan Christoph, additional, Lingor, Paul, additional, Göricke, Bettina, additional, Zierz, Stephan, additional, Jordan, Berit, additional, Baum, Petra, additional, Wolf, Joachim, additional, Winkler, Andrea, additional, Young, Peter, additional, Bogdahn, Ulrich, additional, Prudlo, Johannes, additional, and Kassubek, Jan, additional

Published
2020
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28. The Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc

Author

Ambrozkiewicz, Mateusz C., primary, Ripamonti, Silvia, additional, Borisova, Ekaterina, additional, Schwark, Manuela, additional, Schaub, Theres, additional, Altas, Bekir, additional, Yilmaz, Rüstem, additional, Piepkorn, Lars, additional, Horan, Stephen, additional, Jahn, Olaf, additional, Dere, Ekrem, additional, Rosário, Marta, additional, Borck, Guntram, additional, Ehrenreich, Hannelore, additional, Willig, Katrin, additional, Rhee, JeongSeop, additional, Tarabykin, Victor, additional, and Kawabe, Hiroshi, additional

Published
2019
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31. A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice

Author

Brenner, David, Sieverding, Kirsten, Srinidhi, Jahnavi, Zellner, Susanne, Secker, Christopher, Yilmaz, Rüstem, Dyckow, Julia, Amr, Shady, Ponomarenko, Anna, Tunaboylu, Esra, Douahem, Yasmin, Schlag, Joana S., Rodríguez Martínez, Lucía, Kislinger, Georg, Niemann, Cornelia, Nalbach, Karsten, Ruf, Wolfgang P., Uhl, Jonathan, Hollenbeck, Johanna, Schirmer, Lucas, Catanese, Alberto, Lobsiger, Christian S., Danzer, Karin M., Yilmazer-Hanke, Deniz, Münch, Christian, Koch, Philipp, Freischmidt, Axel, Fetting, Martina, Behrends, Christian, Parlato, Rosanna, and Weishaupt, Jochen H.

Abstract

Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC–derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α–dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.

Published
2024
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32. Further delineation of the KAT6B molecular and phenotypic spectrum

Author

DDD study, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt-Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T, Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E, Kohlhase, Jürgen, Lo, Ivan FM, Smith, Janine, Clayton-Smith, Jill, Regional Genetic Service, St Mary's Hospital, Manchester, Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Haukeland University Hospital, Royal Brsibane and Womens' Hospital, The University of Queensland, Department of Clinical Genetics, Children’s Hospital at Westmead, Service de génétique médicale, AP-HP Hôpital Necker - Enfants Malades [Paris], Institute of Human Genetics, Universität Ulm, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Karolinska University Hospital, Karolinska University Hospital [Stockholm], University Hospitals Bristol, University of Birmingham [Birmingham], Hacettepe University Children's Hospital, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Division of Genetics, Birth Defects and Metabolism, Children's hospital of Chicago, Clinical Genetics, Guy's Hospital [London], North West london hospitals NHS Trust, Department of Clinical Genetics, Northampton General Hospital, Northampton, Barzilai Medical Center, Cliniques Universitaires St Luc, Université Catholique de Louvain (UCL), Service de génétique [Tours], Hôpital Bretonneau - CHRU Tours, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1) - Centre National de la Recherche Scientifique (CNRS) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1) - CHU Pontchaillou [Rennes] - Hôpital Sud, Pediatrics, Istanbul University Cerrahpasa, Birmingham Women’s Hospital, University of Groningen [Groningen], Belfast City Hospital, Centre For Medical Genetics, Clinical Genetic Service, Department of Health, Institute of Medical Genetics, Heath Park, Cardiff, National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Dipartimento di Medicina Molecolare, University of Pavia, UZ Leuven - campus Gasthuisberg, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children’s Hospital, Service de Génétique, CHU Reims - Hôpital Maison Blanche - IFR 53, Leiden University Medical Center, Service de Génétique humaine, Université de Lausanne (UNIL), Çocuk Sağlığı ve Hastalıkları, University of Bergen (UiB), Westmead Hospital [Sydney], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Ulm - Ulm University [Ulm, Allemagne], Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Sheffield Children's NHS Foundation Trust, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Leiden University Medical Center (LUMC), UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Nottingham University Hospitals NHS Trust (NUH), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Università degli Studi di Pavia = University of Pavia (UNIPV), Universiteit Leiden-Universiteit Leiden, Université de Lausanne = University of Lausanne (UNIL), DDD study, and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, DNA Mutational Analysis, Medizin, Gene Expression, Kidney, Severity of Illness Index, Craniofacial Abnormalities, Missense mutation, Exome, Genetics (clinical), Histone Acetyltransferases, Genetics, OHDO SYNDROME, Patella, Exons, Hypotonia, 3. Good health, Blepharophimosis/diagnosis, Blepharophimosis/genetics, Child, Preschool, Congenital Hypothyroidism/diagnosis, Congenital Hypothyroidism/genetics, Craniofacial Abnormalities/diagnosis, Craniofacial Abnormalities/genetics, Diagnosis, Differential, Facies, Female, Genetic Association Studies, Genotype, Heart Defects, Congenital/diagnosis, Heart Defects, Congenital/genetics, Histone Acetyltransferases/genetics, Humans, Intellectual Disability/diagnosis, Intellectual Disability/genetics, Joint Instability/diagnosis, Joint Instability/genetics, Kidney/abnormalities, Kidney/pathology, Mutation, Patella/abnormalities, Patella/pathology, Phenotype, Psychomotor Disorders/diagnosis, Psychomotor Disorders/genetics, Scrotum/abnormalities, Scrotum/pathology, Urogenital Abnormalities/diagnosis, Urogenital Abnormalities/genetics, Scrotum, Medical genetics, genitopatellar, Say-Barber-Biesecker, medicine.symptom, Psychomotor disorder, Haploinsufficiency, Heart Defects, Congenital, Joint Instability, medicine.medical_specialty, Biology, Blepharophimosis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, KAT6B, Article, Intellectual Disability, medicine, Congenital Hypothyroidism, CAUSE GENITOPATELLAR SYNDROME, medicine.disease, blepharophimosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Urogenital Abnormalities, Genitopatellar syndrome, HISTONE ACETYLTRANSFERASE KAT6B, Psychomotor Disorders, MENTAL-RETARDATION
Abstract

International audience; KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Published
2015
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33. Further delineation of the KAT6B molecular and phenotypic spectrum

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt-Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T, Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E, Kohlhase, Jürgen, Lo, Ivan F M, Smith, Janine, Clayton-Smith, Jill, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt-Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T, Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E, Kohlhase, Jürgen, Lo, Ivan F M, Smith, Janine, and Clayton-Smith, Jill

Abstract

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Published
2015

34. Further delineation of the KAT6B molecular and phenotypic spectrum

Author

Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van Den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T., Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E., Kohlhase, Jürgen, Lo, Ivan F.M., Smith, Janine, Clayton-Smith, Jill, Gannon, Tamsin, Perveen, Rahat, Schlecht, Hélene, Ramsden, Simon, Anderson, Beverley, Kerr, Bronwyn, Day, Ruth, Banka, Siddharth, Suri, Mohnish, Berland, Siren, Gabbett, Michael, Ma, Alan, Lyonnet, Stan, Cormier-Daire, Valerie, Yilmaz, Rüstem, Borck, Guntram, Wieczorek, Dagmar, Anderlid, Britt Marie, Smithson, Sarah, Vogt, Julie, Moore-Barton, Heather, Simsek-Kiper, Pelin Ozlem, Maystadt, Isabelle, Destrée, Anne, Bucher, Jessica, Angle, Brad, Mohammed, Shehla, Wakeling, Emma, Price, Sue, Singer, Amihood, Sznajer, Yves, Toutain, Annick, Haye, Damien, Newbury-Ecob, Ruth, Fradin, Melanie, McGaughran, Julie, Tuysuz, Beyhan, Tein, Mark, Bouman, Katelijne, Dabir, Tabib, Van Den Ende, Jenneke, Luk, Ho Ming, Pilz, Daniela T., Eason, Jacqueline, Davies, Sally, Reardon, Willie, Garavelli, Livia, Zuffardi, Orsetta, Devriendt, Koen, Armstrong, Ruth, Johnson, Diana, Doco-Fenzy, Martine, Bijlsma, Emilia, Unger, Sheila, Veenstra-Knol, Hermine E., Kohlhase, Jürgen, Lo, Ivan F.M., Smith, Janine, and Clayton-Smith, Jill

Abstract

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Published
2015

37. An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group

Author

Borck, Guntram, primary, Kakar, Naseebullah, additional, Hoch, Jochen, additional, Friedrich, Katrin, additional, Freudenberg, Jan, additional, Nürnberg, Gudrun, additional, Yilmaz, Rüstem, additional, Daud, Shakeela, additional, Baloch, Dost Muhammad, additional, Nürnberg, Peter, additional, Oldenburg, Johannes, additional, Ahmad, Jamil, additional, and Kubisch, Christian, additional

Published
2011
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38. A Recurrent Synonymous KAT6B Mutation Causes Say-Barber-Biesecker/Young-Simpson Syndrome by Inducing Aberrant Splicing.

Author

Yilmaz, Rüstem, Beleza‐Meireles, Ana, Price, Susan, Oliveira, Renata, Kubisch, Christian, Clayton‐Smith, Jill, Szakszon, Katalin, and Borck, Guntram

Abstract

Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-"mental retardation" syndromes and the more severe genitopatellar syndrome. The SBBYS syndromecausing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome. [ABSTRACT FROM AUTHOR]

Published
2015
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39. Reply: Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations.

Author

Brenner, David, Rosenbohm, Angela, Yilmaz, Rüstem, Müller, Kathrin, Grehl, Torsten, Petri, Susanne, Meyer, Thomas, Grosskreutz, Julian, Weydt, Patrick, Ruf, Wolfgang, Neuwirth, Christoph, Weber, Markus, Pinto, Susana, Claeys, Kristl G, Schrank, Berthold, Jordan, Berit, Knehr, Antje, Günther, Kornelia, Hübers, Annemarie, and Zeller, Daniel

Subjects
SPINAL muscular atrophy, PHENOTYPES, AMYOTROPHIC lateral sclerosis, MOTOR neuron diseases, MOTOR neurons
Published
2019
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40. Hot-spot KIF5A mutations cause familial ALS

Author

Brenner, David, Yilmaz, Rüstem, Müller, Kathrin, Grehl, Torsten, Petri, Susanne, Meyer, Thomas, Grosskreutz, Julian, Weydt, Patrick, Ruf, Wolfgang, Neuwirth, Christoph, Weber, Markus, Pinto, Susana, Claeys, Kristl, Schrank, Berthold, Jordan, Berit, Knehr, Antje, Günther, Kornelia, Hübers, Annemarie, Zeller, Daniel, Kubisch, Christian, Jablonka, Sibylle, Sendtner, Michael, Klopstock, Thomas, De Carvalho, Mamede, Sperfeld, Anne, Borck, Guntram, Volk, Alexander E., Dorst, Johannes, Weis, Joachim, Otto, Markus, Schuster, Joachim, Del Tredici, Kelly, Braak, Heiko, Danzer, Karin M., Freischmidt, Axel, Meitinger, Thomas, Strom, Tim M., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Weyen, Ute, Hermann, Andreas, Hagenacker, Tim, Koch, Jan Christoph, Lingor, Paul, Göricke, Bettina, Zierz, Stephan, Baum, Petra, Wolf, Joachim, Winkler, Andrea, Young, Peter, Bogdahn, Ulrich, Prudlo, Johannes, and Kassubek, Jan

Subjects
3. Good health
Abstract

Brain : a journal of neurology 141(3), 688-697 (2018). doi:10.1093/brain/awx370, Published by Oxford Univ. Press, Oxford

41. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

Author

Basel-Vanagaite, Lina, Yilmaz, Rüstem, Tang, Sha, Reuter, Miriam, Rahner, Nils, Grange, Dorothy, Mortenson, Megan, Koty, Patrick, Feenstra, Heather, Farwell Gonzalez, Kelly, Sticht, Heinrich, Boddaert, Nathalie, Désir, Julie, Anyane-Yeboa, Kwame, Zweier, Christiane, Reis, André, Kubisch, Christian, Jewett, Tamison, Zeng, Wenqi, Borck, Guntram, Basel-Vanagaite, Lina, Yilmaz, Rüstem, Tang, Sha, Reuter, Miriam, Rahner, Nils, Grange, Dorothy, Mortenson, Megan, Koty, Patrick, Feenstra, Heather, Farwell Gonzalez, Kelly, Sticht, Heinrich, Boddaert, Nathalie, Désir, Julie, Anyane-Yeboa, Kwame, Zweier, Christiane, Reis, André, Kubisch, Christian, Jewett, Tamison, Zeng, Wenqi, and Borck, Guntram

Abstract

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome”.

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