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2. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Author

Stegmann, Jil D., Kalanithy, Jeshurun C., Dworschak, Gabriel C., Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M., Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T., Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J., Klee, Eric W., Lanpher, Brendan C., Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R., Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L., Riley, Kacie, Klee, Victoria, Walsh, Laurence E., Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stoppe, Arzu, Stuurman, Kyra, van Slegtenhorst, Marjon, Barakat, Tahsin Stefan, Mulhern, Maureen S., Sands, Tristan T., Cytrynbaum, Cheryl, Weksberg, Rosanna, Isidori, Federica, Pippucci, Tommaso, Severi, Giulia, Montanari, Francesca, Kruer, Michael C., Bakhtiari, Somayeh, Darvish, Hossein, Reutter, Heiko, Hagelueken, Gregor, Geyer, Matthias, Woolf, Adrian S., Posey, Jennifer E., Lupski, James R., Odermatt, Benjamin, and Hilger, Alina C.

Published
2024
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3. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Published
2023
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4. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Author

Stegmann, Jil D, Kalanithy, Jeshurun C, Dworschak, Gabriel C, Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M, Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T, Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J, Klee, Eric W, Lanpher, Brendan C, Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R, Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L, Riley, Kacie, Klee, Victoria, Walsh, Laurence E, Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stuurman, Kyra, van Slegtenhorst, Marjon, Stegmann, Jil D, Kalanithy, Jeshurun C, Dworschak, Gabriel C, Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M, Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T, Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J, Klee, Eric W, Lanpher, Brendan C, Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R, Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L, Riley, Kacie, Klee, Victoria, Walsh, Laurence E, Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stuurman, Kyra, and van Slegtenhorst, Marjon

Abstract

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.

Published
2024

6. Kinesin family member 12‐related hepatopathy: A generally indolent disorder with elevated gamma‐glutamyl‐transferase activity.

Author

Vogel, Georg‐Friedrich, Podpeskar, Alexandra, Rieder, Dietmar, Salzer, Helin, Garczarczyk‐Asim, Dorota, Wang, Li, Abuduxikuer, Kuerbanjiang, Wang, Jian‐She, Scharrer, Anke, Faqeih, Eissa Ali, Aseeri, Ali T., Vodopiutz, Julia, Heilos, Andreas, Pichler, Judith, Huber, Wolf‐Dietrich, Müller, Thomas, Knisely, A. S., and Janecke, Andreas R.

Subjects
HEPATIC fibrosis, LIVER failure, CHILD patients, LIVER transplantation, LIVER diseases, GAMMA-glutamyltransferase
Abstract

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma‐glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12‐related disease from other entities with elevated GGT. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy

Author

Schmidts, Miriam, Vodopiutz, Julia, Christou-Savina, Sonia, Cortés, Claudio R, McInerney-Leo, Aideen M, Emes, Richard D, Arts, Heleen H, Tüysüz, Beyhan, D’Silva, Jason, Leo, Paul J, Giles, Tom C, Oud, Machteld M, Harris, Jessica A, Koopmans, Marije, Marshall, Mhairi, Elçioglu, Nursel, Kuechler, Alma, Bockenhauer, Detlef, Moore, Anthony T, Wilson, Louise C, Janecke, Andreas R, Hurles, Matthew E, Emmet, Warren, Gardiner, Brooke, Streubel, Berthold, Dopita, Belinda, Zankl, Andreas, Kayserili, Hülya, Scambler, Peter J, Brown, Matthew A, Beales, Philip L, Wicking, Carol, UK10K, Duncan, Emma L, and Mitchison, Hannah M

Subjects
Rare Diseases, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Asians, Axoneme, Carrier Proteins, Child, Chlamydomonas, Cilia, Cytoplasmic Dyneins, Cytoskeleton, Ellis-Van Creveld Syndrome, Exome, Exons, Humans, Infant, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Mutation, Protein Conformation, Proteomics, Whites, UK10K, Asian People, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Published
2013

9. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

10. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

13. Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease

Author

Panzer, Marlene, Viveiros, André, Schaefer, Benedikt, Baumgartner, Nadja, Seppi, Klaus, Djamshidian, Atbin, Todorov, Theodor, Griffiths, William JH, Schott, Eckart, Schuelke, Markus, Eurich, Dennis, Stättermayer, Albert Friedrich, Bomford, Adrian, Foskett, Pierre, Vodopiutz, Julia, Stauber, Rudolf, Pertler, Elke, Morell, Bernhard, Tilg, Herbert, Müller, Thomas, Kiechl, Stefan, Jimenez-Heredia, Raul, Weiss, Karl Heinz, Hahn, Si Houn, Janecke, Andreas, Ferenci, Peter, Zoller, Heinz, Viveiros, André [0000-0001-7141-8867], Schaefer, Benedikt [0000-0001-8690-2774], Seppi, Klaus [0000-0001-6503-1455], Djamshidian, Atbin [0000-0001-7174-6000], Todorov, Theodor [0000-0002-0548-5487], Griffiths, William JH [0000-0001-9927-0868], Schott, Eckart [0000-0001-7769-4029], Schuelke, Markus [0000-0003-2824-3891], Eurich, Dennis [0000-0003-2559-1567], Stättermayer, Albert Friedrich [0000-0003-0737-4091], Bomford, Adrian [0000-0002-7035-5080], Vodopiutz, Julia [0000-0002-8087-7026], Stauber, Rudolf [0000-0002-3687-9331], Pertler, Elke [0000-0002-1162-9571], Morell, Bernhard [0000-0002-8507-0619], Tilg, Herbert [0000-0002-4235-2579], Müller, Thomas [0000-0002-3961-4814], Kiechl, Stefan [0000-0002-9836-2514], Jimenez-Heredia, Raul [0000-0002-1406-0608], Weiss, Karl Heinz [0000-0002-6336-9935], Ferenci, Peter [0000-0003-2306-1992], and Apollo - University of Cambridge Repository

Subjects
Hepatology, Hepatolenticular Degeneration, Copper-Transporting ATPases, Mutation, Humans, Exons, Copper, Silent Mutation
Abstract

Funder: Österreichische Forschungsförderungsgesellschaft; Id: http://dx.doi.org/10.13039/501100004955, Funder: Verein zur Foerderung der Wissenschaft in Gastroenterologie & Hepatologie, Funder: Christian Doppler Forschungsgesellschaft; Id: http://dx.doi.org/10.13039/501100006012, Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10-6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10-5 ; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.

Published
2022

14. CUX1-related neurodevelopmental disorder: Deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, primary, Marcos-Grañeda, Elia, additional, Weiss, Linnea, additional, Gurnett, Christina, additional, Jelsig, Anne Marie, additional, Vineke, Susanne, additional, Isidor, Bertrand, additional, Mercier, Sandra, additional, Magnussen, Kari, additional, Zacher, Pia, additional, Hashim, Mona, additional, Pagnamenta, Alistair, additional, Race, Simone, additional, Srivast, Siddharth, additional, Frazier, Zoë, additional, Maiwald, Robert, additional, Pergande, Matthias, additional, Milani, Donatella, additional, Rinelli, Martina, additional, Levy, Jonathan, additional, Krey, Ilona, additional, Fontana, Paolo, additional, Lonardo, Fortunato, additional, Riley, Stephanie, additional, Kretzer, Jasmine, additional, Rankin, Julia, additional, Reis, Linda, additional, Semina, Elena, additional, Reuter, Miriam, additional, Scherer, Stephen, additional, Iascone, Maria, additional, Weis, Denisa, additional, Fagerberg, Christina, additional, Brasch-Andersen, Charlotte, additional, Hansen, Lars, additional, Kuechler, Alma, additional, Noble, Nathan, additional, Gardham, Alice, additional, Tenney, Jessica, additional, Rathore, Geetanjali, additional, Beck-Woedl, Stefanie, additional, Haack, Tobias, additional, Pavlidou, Despina, additional, Atallah, Isis, additional, Vodopiutz, Julia, additional, Janecke, Andreas, additional, Lemke, Johannes, additional, Jamra, Rami Abou, additional, Nieto, Marta, additional, Tümer, Zeynep, additional, and Platzer, Konrad, additional

Published
2022
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15. Chondroitin Sulfate N‐acetylgalactosaminyltransferase‐1 (CSGalNAcT‐1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity

Author

Vodopiutz, Julia, Mizumoto, Shuji, Lausch, Ekkehart, Rossi, Antonio, Unger, Sheila, Janocha, Nikolaus, Costantini, Rossella, Seidl, Rainer, Greber‐Platzer, Susanne, Yamada, Shuhei, Müller, Thomas, Jilma, Bernd, Ganger, Rudolf, Superti‐Furga, Andrea, Ikegawa, Shiro, Sugahara, Kazuyuki, and Janecke, Andreas R.

Published
2017
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18. Synonymous mutation in adenosine triphosphatase copper‐transporting beta causes enhanced exon skipping in Wilson disease

Author

Panzer, Marlene, primary, Viveiros, André, additional, Schaefer, Benedikt, additional, Baumgartner, Nadja, additional, Seppi, Klaus, additional, Djamshidian, Atbin, additional, Todorov, Theodor, additional, Griffiths, William J. H., additional, Schott, Eckart, additional, Schuelke, Markus, additional, Eurich, Dennis, additional, Stättermayer, Albert Friedrich, additional, Bomford, Adrian, additional, Foskett, Pierre, additional, Vodopiutz, Julia, additional, Stauber, Rudolf, additional, Pertler, Elke, additional, Morell, Bernhard, additional, Tilg, Herbert, additional, Müller, Thomas, additional, Kiechl, Stefan, additional, Jimenez‐Heredia, Raul, additional, Weiss, Karl Heinz, additional, Hahn, Si Houn, additional, Janecke, Andreas, additional, Ferenci, Peter, additional, and Zoller, Heinz, additional

Published
2022
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20. Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea

Author

Janecke, Andreas R., Heinz-Erian, Peter, Yin, Jianyi, Petersen, Britt-Sabina, Franke, Andre, Lechner, Silvia, Fuchs, Irene, Melancon, Serge, Uhlig, Holm H., Travis, Simon, Marinier, Evelyne, Perisic, Vojislav, Ristic, Nina, Gerner, Patrick, Booth, Ian W., Wedenoja, Satu, Baumgartner, Nadja, Vodopiutz, Julia, Frechette-Duval, Marie-Christine, De Lafollie, Jan, Persad, Rabindranath, Warner, Neil, Tse, C. Ming, Sud, Karan, Zachos, Nicholas C., Sarker, Rafiquel, Zhu, Xinjun, Muise, Aleixo M., Zimmer, Klaus-Peter, Witt, Heiko, Zoller, Heinz, Donowitz, Mark, and Müller, Thomas

Published
2015
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21. WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Author

Vodopiutz, Julia, Seidl, Rainer, Prayer, Daniela, Khan, Imran M., Mayr, Johannes A., Streubel, Berthold, Stei, Jens-Oliver, Hahn, Andreas, Csaicsich, Dagmar, Castro, Christel, Assoum, Mirna, Müller, Thomas, Wieczorek, Dagmar, Mancini, Grazia M. S., Sadowski, Carolin E., Lévy, Nicolas, Mégarbané, André, Godbole, Koumudi, Schanze, Denny, Hildebrandt, Friedhelm, Delague, Valérie, Janecke, Andreas R., and Zenker, Martin

Published
2015
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24. Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome

Author

Dundar, Munis, Muller, Thomas, Qi Zhang, Jing Pan, Steinmann, Beat, Vodopiutz, Julia, Gruber, Robert, Sonoda, Tohru, Krabichler, Birgit, Utermann, Gerd, Baenziger, Jacques U. Lijuan Zhang, and Janecke, Andreas R.

Subjects
Clubfoot -- Genetic aspects, Human genome -- Research, Single nucleotide polymorphisms -- Analysis, Transferases -- Research, Biological sciences
Abstract

An SNP array-based genome-wide linkage analysis is conducted to explain the molecular basis and symptoms of the adducted thumb-clubfoot syndrome. The results demonstrate that a particular defect of dermatan sulfate biosynthesis is the main factor that leads to the onset of the autosomal-recessive disorder.

Published
2009

30. An Overview of L-2-Hydroxyglutarate Dehydrogenase Gene (L2HGDH) Variants: A Genotype–Phenotype Study

Author

Steenweg, Marjan E., Jakobs, Cornelis, Errami, Abdellatif, van Dooren, Silvy J.M., Adeva Bartolomé, Maria T., Aerssens, Peter, Augoustides-Savvapoulou, Persephone, Baric, Ivo, Baumann, Matthias, Bonafé, Luisa, Chabrol, Brigitte, Clarke, Joe T.R., Clayton, Peter, Coker, Mahmut, Cooper, Sarah, Falik-Zaccai, Tzipora, Gorman, Mark, Hahn, Andreas, Hasanoglu, Alev, King, Mary D., de Klerk, Hans B.C., Korman, Stanley H., Lee, Céline, Meldgaard Lund, Allan, Mejaški-Bošnjak, Vlatka, Pascual-Castroviejo, Ignacio, Raadhyaksha, Aparna, Rootwelt, Terje, Roubertie, Agathe, Ruiz-Falco, Maria L., Scalais, Emmanuel, Schimmel, Ulf, Seijo-Martinez, Manuel, Suri, Mohnish, Sykut-Cegielska, Jolanta, Trefz, Friedrich K., Uziel, Graziella, Valayannopoulos, Vassili, Vianey-Saban, Christine, Vlaho, Stefan, Vodopiutz, Julia, Wajner, Moacir, Walter, John, Walter-Derbort, Claudia, Yapici, Zuhal, Zafeiriou, Dimitrios I., Spreeuwenberg, Marieke D., Celli, Jacopo, Dunnen, Johan T. den, der Knaap, Marjo S. van, and Salomons, Gajja S.

Published
2010
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31. SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase

Author

Holt-Danborg, Lasse, Vodopiutz, Julia, Nonboe, Annika W, De Laffolie, Jan, Skovbjerg, Signe, Wolters, Victorien M, Müller, Thomas, Hetzer, Benjamin, Querfurt, Alexander, Zimmer, Klaus-Peter, Jensen, Jan K, Entenmann, Andreas, Heinz-Erian, Peter, Vogel, Lotte K, Janecke, Andreas R, Holt-Danborg, Lasse, Vodopiutz, Julia, Nonboe, Annika W, De Laffolie, Jan, Skovbjerg, Signe, Wolters, Victorien M, Müller, Thomas, Hetzer, Benjamin, Querfurt, Alexander, Zimmer, Klaus-Peter, Jensen, Jan K, Entenmann, Andreas, Heinz-Erian, Peter, Vogel, Lotte K, and Janecke, Andreas R

Abstract

The syndromic form of congenital sodium diarrhea (SCSD) is caused by bi-allelic mutations in SPINT2, which encodes a Kunitz type serine protease inhibitor (HAI-2). We report three novel SCSD patients, two novel SPINT2 mutations, and review published cases. The most common findings in SCSD patients were choanal atresia (20/34), and keratitis of infantile onset (26/34). Characteristic epithelial tufts on intestinal histology were reported in 13/34 patients. Of 13 different SPINT2 variants identified in SCSD, four are missense variants and localize to the second Kunitz domain (KD2) of HAI-2. HAI-2 has been implicated in the regulation of the activities of several serine proteases including prostasin and matriptase, which are both important for epithelial barrier formation. No patient with bi-allelic stop mutations was identified, suggesting that at least one SPINT2 allele encoding a protein with residual HAI-2 function is necessary for survival. We show that the SCSD-associated HAI-2 variants p.Phe161Val, p.Tyr163Cys, and p.Gly168Ser all display decreased ability to inhibit prostasin-catalyzed cleavage. However, the SCSD-associated HAI-2 variants inhibited matriptase as efficiently as the wild-type HAI-2. Homology modeling indicated limited solvent exposure of the mutated amino acids, suggesting that they induce misfolding of KD2. This suggests that prostasin needs to engage with an exosite motif located on KD2 in addition to the binding loop (Cys47/Arg48) located on the first Kunitz domain in order to inhibit prostasin. In conclusion our data suggests that SCSD is caused by lack of inhibition of prostasin or a similar protease in the secretory pathway or on the plasma membrane.

Published
2019

32. De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Author

Genetica, UMC Utrecht, Genetica Klinische Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Cancer, Diets, Illja J., van der Donk, Roos, Baltrunaite, Kristina, Waanders, Esmé, Reijnders, Margot R.F., Dingemans, Alexander J.M., Pfundt, Rolph, Vulto-van Silfhout, Anneke T., Wiel, Laurens, Gilissen, Christian, Thevenon, Julien, Perrin, Laurence, Afenjar, Alexandra, Nava, Caroline, Keren, Boris, Bartz, Sarah, Peri, Bethany, Beunders, Gea, Verbeek, Nienke, van Gassen, Koen, Thiffault, Isabelle, Cadieux-Dion, Maxime, Huerta-Saenz, Lina, Wagner, Matias, Konstantopoulou, Vassiliki, Vodopiutz, Julia, Griese, Matthias, Boel, Annekatrien, Callewaert, Bert, Brunner, Han G., Kleefstra, Tjitske, Hoogerbrugge, Nicoline, de Vries, Bert B.A., Hwa, Vivian, Dauber, Andrew, Hehir-Kwa, Jayne Y., Kuiper, Roland P., Jongmans, Marjolijn C.J., Genetica, UMC Utrecht, Genetica Klinische Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Cancer, Diets, Illja J., van der Donk, Roos, Baltrunaite, Kristina, Waanders, Esmé, Reijnders, Margot R.F., Dingemans, Alexander J.M., Pfundt, Rolph, Vulto-van Silfhout, Anneke T., Wiel, Laurens, Gilissen, Christian, Thevenon, Julien, Perrin, Laurence, Afenjar, Alexandra, Nava, Caroline, Keren, Boris, Bartz, Sarah, Peri, Bethany, Beunders, Gea, Verbeek, Nienke, van Gassen, Koen, Thiffault, Isabelle, Cadieux-Dion, Maxime, Huerta-Saenz, Lina, Wagner, Matias, Konstantopoulou, Vassiliki, Vodopiutz, Julia, Griese, Matthias, Boel, Annekatrien, Callewaert, Bert, Brunner, Han G., Kleefstra, Tjitske, Hoogerbrugge, Nicoline, de Vries, Bert B.A., Hwa, Vivian, Dauber, Andrew, Hehir-Kwa, Jayne Y., Kuiper, Roland P., and Jongmans, Marjolijn C.J.

Published
2019

33. SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase

Author

Child Health, MDL patientenzorg, Holt-Danborg, Lasse, Vodopiutz, Julia, Nonboe, Annika W., De Laffolie, Jan, Skovbjerg, Signe, Wolters, Victorien M., Müller, Thomas, Hetzer, Benjamin, Querfurt, Alexander, Zimmer, Klaus Peter, Jensen, Jan K., Entenmann, Andreas, Heinz-Erian, Peter, Vogel, Lotte K., Janecke, Andreas R., Child Health, MDL patientenzorg, Holt-Danborg, Lasse, Vodopiutz, Julia, Nonboe, Annika W., De Laffolie, Jan, Skovbjerg, Signe, Wolters, Victorien M., Müller, Thomas, Hetzer, Benjamin, Querfurt, Alexander, Zimmer, Klaus Peter, Jensen, Jan K., Entenmann, Andreas, Heinz-Erian, Peter, Vogel, Lotte K., and Janecke, Andreas R.

Published
2019

35. CSGALNACT1‐congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age

Author

Mizumoto, Shuji, primary, Janecke, Andreas R., additional, Sadeghpour, Azita, additional, Povysil, Gundula, additional, McDonald, Marie T., additional, Unger, Sheila, additional, Greber‐Platzer, Susanne, additional, Deak, Kristen L., additional, Katsanis, Nicholas, additional, Superti‐Furga, Andrea, additional, Sugahara, Kazuyuki, additional, Davis, Erica E., additional, Yamada, Shuhei, additional, and Vodopiutz, Julia, additional

Published
2019
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36. De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Author

Diets, Illja J., primary, van der Donk, Roos, additional, Baltrunaite, Kristina, additional, Waanders, Esmé, additional, Reijnders, Margot R.F., additional, Dingemans, Alexander J.M., additional, Pfundt, Rolph, additional, Vulto-van Silfhout, Anneke T., additional, Wiel, Laurens, additional, Gilissen, Christian, additional, Thevenon, Julien, additional, Perrin, Laurence, additional, Afenjar, Alexandra, additional, Nava, Caroline, additional, Keren, Boris, additional, Bartz, Sarah, additional, Peri, Bethany, additional, Beunders, Gea, additional, Verbeek, Nienke, additional, van Gassen, Koen, additional, Thiffault, Isabelle, additional, Cadieux-Dion, Maxime, additional, Huerta-Saenz, Lina, additional, Wagner, Matias, additional, Konstantopoulou, Vassiliki, additional, Vodopiutz, Julia, additional, Griese, Matthias, additional, Boel, Annekatrien, additional, Callewaert, Bert, additional, Brunner, Han G., additional, Kleefstra, Tjitske, additional, Hoogerbrugge, Nicoline, additional, de Vries, Bert B.A., additional, Hwa, Vivian, additional, Dauber, Andrew, additional, Hehir-Kwa, Jayne Y., additional, Kuiper, Roland P., additional, and Jongmans, Marjolijn C.J., additional

Published
2019
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37. CSGALNACT1‐congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.

Author

Mizumoto, Shuji, Janecke, Andreas R., Sadeghpour, Azita, Povysil, Gundula, McDonald, Marie T., Unger, Sheila, Greber‐Platzer, Susanne, Deak, Kristen L., Katsanis, Nicholas, Superti‐Furga, Andrea, Sugahara, Kazuyuki, Davis, Erica E., Yamada, Shuhei, and Vodopiutz, Julia

Abstract

Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio‐exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT‐1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT‐1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients' fibroblasts compared to controls. Our data indicate that biallelic loss‐of‐function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1‐CDG. [ABSTRACT FROM AUTHOR]

Published
2020
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38. SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase

Author

Holt-Danborg, Lasse, primary, Vodopiutz, Julia, additional, Nonboe, Annika W, additional, De Laffolie, Jan, additional, Skovbjerg, Signe, additional, Wolters, Victorien M, additional, Müller, Thomas, additional, Hetzer, Benjamin, additional, Querfurt, Alexander, additional, Zimmer, Klaus-Peter, additional, Jensen, Jan K, additional, Entenmann, Andreas, additional, Heinz-Erian, Peter, additional, Vogel, Lotte K, additional, and Janecke, Andreas R, additional

Published
2018
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40. Hidden Mutations in CdLS - Limitations of Sanger Sequencing in Molecular Diagnostics

Author

Braunholz, Diana, Obieglo, Carolin, Parenti, Ilaria, Pozojevic, Jelena, Eckhold, Juliane, Reiz, Benedikt, Braenne, Ingrid, Wendt, Kerstin S., Watrin, Erwan, Vodopiutz, Julia, Rieder, Harald, Gillessen-Kaesbach, Gabriele, Kaiser, Frank J., Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Institut für Humangenetik Lübeck, Universität zu Lübeck [Lübeck], TARGET-CdLS, Bundesministerium für Bildung und Forschung, TARGET-CdLS, Netherlands Organisation for Health Research and Development, TARGET-CdLS, Agence Nationale de la Recherche, 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 ), and Universität zu Lübeck = University of Lübeck [Lübeck]

Subjects
CdLS, panel sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, cohesin, mosaic, NIPBL
Abstract

International audience; Cornelia de Lange syndrome (CdLS) is a well characterized developmental disorder. The genetic cause of CdLS is a mutation in one of five associated genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8) accounting for about 70 % of cases. To improve our current molecular diagnostic and to analyze some of CdLS candidate genes we developed and established a gene panel approach. Because recent data indicate a high frequency of mosaic NIPBL mutations that were not detected by conventional sequencing approaches of blood DNA, we started to collected buccal mucosa samples of our patients that were negative for mutations in the known CdLS genes. Here we report the identification of three mosaic NIPBL mutations by our high-coverage gene panel sequencing approach that were undetected by classical Sanger sequencing analysis of buccal mucosa DNA. All mutations were confirmed by the use of highly sensitive SNaPshot fragment analysis using DNA from buccal mucosa, urine and fibroblast samples. In blood samples we could not detect the respective mutation. Finally, in fibroblast samples from all three patients, Sanger sequencing could identify all the mutations. Thus, our study highlights the need for highly sensitive technologies in molecular diagnostic of CdLS to improve genetic diagnosis and counseling of patients and their families. This article is protected by copyright. All rights reserved.

Published
2015
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41. Chondroitin SulfateN-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity

Author

Vodopiutz, Julia, primary, Mizumoto, Shuji, additional, Lausch, Ekkehart, additional, Rossi, Antonio, additional, Unger, Sheila, additional, Janocha, Nikolaus, additional, Costantini, Rossella, additional, Seidl, Rainer, additional, Greber-Platzer, Susanne, additional, Yamada, Shuhei, additional, Müller, Thomas, additional, Jilma, Bernd, additional, Ganger, Rudolf, additional, Superti-Furga, Andrea, additional, Ikegawa, Shiro, additional, Sugahara, Kazuyuki, additional, and Janecke, Andreas R., additional

Published
2016
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42. ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation

Author

Jansen, Eric J. R., primary, Timal, Sharita, additional, Ryan, Margret, additional, Ashikov, Angel, additional, van Scherpenzeel, Monique, additional, Graham, Laurie A., additional, Mandel, Hanna, additional, Hoischen, Alexander, additional, Iancu, Theodore C., additional, Raymond, Kimiyo, additional, Steenbergen, Gerry, additional, Gilissen, Christian, additional, Huijben, Karin, additional, van Bakel, Nick H. M., additional, Maeda, Yusuke, additional, Rodenburg, Richard J., additional, Adamowicz, Maciej, additional, Crushell, Ellen, additional, Koenen, Hans, additional, Adams, Darius, additional, Vodopiutz, Julia, additional, Greber-Platzer, Susanne, additional, Müller, Thomas, additional, Dueckers, Gregor, additional, Morava, Eva, additional, Sykut-Cegielska, Jolanta, additional, Martens, Gerard J. M., additional, Wevers, Ron A., additional, Niehues, Tim, additional, Huynen, Martijn A., additional, Veltman, Joris A., additional, Stevens, Tom H., additional, and Lefeber, Dirk J., additional

Published
2016
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43. Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies

Author

McInerney-Leo, Aideen, Harris, Jessica, Leo, Paul, Marshall, Mhairi, Gardiner, Brooke, Kinning, E., Leong, Huey Yin, McKenzie, Fiona, Ong, W., Vodopiutz, Julia, Wicking, Carol, Brown, Matthew, Zankl, Andreas, Duncan, Emma, McInerney-Leo, Aideen, Harris, Jessica, Leo, Paul, Marshall, Mhairi, Gardiner, Brooke, Kinning, E., Leong, Huey Yin, McKenzie, Fiona, Ong, W., Vodopiutz, Julia, Wicking, Carol, Brown, Matthew, Zankl, Andreas, and Duncan, Emma

Abstract

Short-rib thoracic dystrophies (SRTDs) are congenital disorders due to defects in primary cilium function. SRTDs are recessively inherited with mutations identified in 14 genes to date (comprising 398 exons). Conventional mutation detection (usually by iterative Sanger sequencing) is inefficient and expensive, and often not undertaken. Whole exome massive parallel sequencing has been used to identify new genes for SRTD (WDR34, WDR60 and IFT172); however, the clinical utility of whole exome sequencing (WES) has not been established. WES was performed in 11 individuals with SRTDs. Compound heterozygous or homozygous mutations were identified in six confirmed SRTD genes in 10 individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%. WES data from 993 unaffected individuals sequenced using similar technology showed two individuals with rare (minor allele frequency <0.005) compound heterozygous variants of unknown significance in SRTD genes (specificity >99%). Costs for consumables, laboratory processing and bioinformatic analysis were

Published
2015

45. WDR73Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Author

Vodopiutz, Julia, primary, Seidl, Rainer, additional, Prayer, Daniela, additional, Khan, M. Imran, additional, Mayr, Johannes A., additional, Streubel, Berthold, additional, Steiß, Jens-Oliver, additional, Hahn, Andreas, additional, Csaicsich, Dagmar, additional, Castro, Christel, additional, Assoum, Mirna, additional, Müller, Thomas, additional, Wieczorek, Dagmar, additional, Mancini, Grazia M. S., additional, Sadowski, Carolin E., additional, Lévy, Nicolas, additional, Mégarbané, André, additional, Godbole, Koumudi, additional, Schanze, Denny, additional, Hildebrandt, Friedhelm, additional, Delague, Valérie, additional, Janecke, Andreas R., additional, and Zenker, Martin, additional

Published
2015
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46. Congenital secretory diarrhoea caused by activating germline mutations inGUCY2C

Author

Müller, Thomas, primary, Rasool, Insha, additional, Heinz-Erian, Peter, additional, Mildenberger, Eva, additional, Hülstrunk, Christian, additional, Müller, Andreas, additional, Michaud, Laurent, additional, Koot, Bart G P, additional, Ballauff, Antje, additional, Vodopiutz, Julia, additional, Rosipal, Stefan, additional, Petersen, Britt-Sabina, additional, Franke, Andre, additional, Fuchs, Irene, additional, Witt, Heiko, additional, Zoller, Heinz, additional, Janecke, Andreas R, additional, and Visweswariah, Sandhya S, additional

Published
2015
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48. Hidden Mutations in Cornelia de Lange Syndrome Limitations of Sanger Sequencing in Molecular Diagnostics

Author

Braunholz, Diana, primary, Obieglo, Carolin, additional, Parenti, Ilaria, additional, Pozojevic, Jelena, additional, Eckhold, Juliane, additional, Reiz, Benedikt, additional, Braenne, Ingrid, additional, Wendt, Kerstin S., additional, Watrin, Erwan, additional, Vodopiutz, Julia, additional, Rieder, Harald, additional, Gillessen-Kaesbach, Gabriele, additional, and Kaiser, Frank J., additional

Published
2014
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49. An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

Author

Steenweg, Marjan E, Jakobs, Cornelis, Errami, Abdellatif, van Dooren, Silvy J M, Adeva Bartolomé, Maria T, Aerssens, Peter, Augoustides-Savvapoulou, Persephone, Baric, Ivo, Baumann, Matthias, Bonafé, Luisa, Chabrol, Brigitte, Clarke, Joe T R, Clayton, Peter, Coker, Mahmut, Cooper, Sarah, Falik-Zaccai, Tzipora, Gorman, Mark, Hahn, Andreas, Hasanoglu, Alev, King, Mary D, de Klerk, Hans B C, Korman, Stanley H, Lee, Céline, Meldgaard Lund, Allan, Mejaski-Bosnjak, Vlatka, Pascual-Castroviejo, Ignacio, Raadhyaksha, Aparna, Rootwelt, Terje, Roubertie, Agathe, Ruiz-Falco, Maria L, Scalais, Emmanuel, Schimmel, Ulf, Seijo-Martinez, Manuel, Suri, Mohnish, Sykut-Cegielska, Jolanta, Trefz, Friedrich K, Uziel, Graziella, Valayannopoulos, Vassili, Vianey-Saban, Christine, Vlaho, Stefan, Vodopiutz, Julia, Wajner, Moacir, Walter, John, Walter-Derbort, Claudia, Yapici, Zuhal, Zafeiriou, Dimitrios I, Spreeuwenberg, Marieke D, Celli, Jacopo, den Dunnen, Johan T, van der Knaap, Marjo S, Salomons, Gajja S, Steenweg, Marjan E, Jakobs, Cornelis, Errami, Abdellatif, van Dooren, Silvy J M, Adeva Bartolomé, Maria T, Aerssens, Peter, Augoustides-Savvapoulou, Persephone, Baric, Ivo, Baumann, Matthias, Bonafé, Luisa, Chabrol, Brigitte, Clarke, Joe T R, Clayton, Peter, Coker, Mahmut, Cooper, Sarah, Falik-Zaccai, Tzipora, Gorman, Mark, Hahn, Andreas, Hasanoglu, Alev, King, Mary D, de Klerk, Hans B C, Korman, Stanley H, Lee, Céline, Meldgaard Lund, Allan, Mejaski-Bosnjak, Vlatka, Pascual-Castroviejo, Ignacio, Raadhyaksha, Aparna, Rootwelt, Terje, Roubertie, Agathe, Ruiz-Falco, Maria L, Scalais, Emmanuel, Schimmel, Ulf, Seijo-Martinez, Manuel, Suri, Mohnish, Sykut-Cegielska, Jolanta, Trefz, Friedrich K, Uziel, Graziella, Valayannopoulos, Vassili, Vianey-Saban, Christine, Vlaho, Stefan, Vodopiutz, Julia, Wajner, Moacir, Walter, John, Walter-Derbort, Claudia, Yapici, Zuhal, Zafeiriou, Dimitrios I, Spreeuwenberg, Marieke D, Celli, Jacopo, den Dunnen, Johan T, van der Knaap, Marjo S, and Salomons, Gajja S

Abstract

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.

Published
2010

50. Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C.

Author

Müller, Thomas, Rasool, Insha, Heinz-Erian, Peter, Mildenberger, Eva, Hülstrunk, Christian, Müller, Andreas, Michaud, Laurent, Koot, Bart G. P., Ballauff, Antje, Vodopiutz, Julia, Rosipal, Stefan, Petersen, Britt-Sabina, Franke, Andre, Fuchs, Irene, Witt, Heiko, Zoller, Heinz, Janecke, Andreas R., and Visweswariah, Sandhya S.

Subjects
CONGENITAL disorders, DIARRHEA, GERM cells, GUANYLATE cyclase, GENETIC mutation, GUANYLIC acid, HISTOLOGY, SINGLE nucleotide polymorphisms, POLYMERASE chain reaction
Published
2016
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