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201. Nectin-4 Mutations Causing Ectodermal Dysplasia with Syndactyly Perturb the Rac1 Pathway and the Kinetics of Adherens Junction Formation

Author

Fortugno, Paola, primary, Josselin, Emmanuelle, additional, Tsiakas, Konstantinos, additional, Agolini, Emanuele, additional, Cestra, Gianluca, additional, Teson, Massimo, additional, Santer, René, additional, Castiglia, Daniele, additional, Novelli, Giuseppe, additional, Dallapiccola, Bruno, additional, Kurth, Ingo, additional, Lopez, Marc, additional, Zambruno, Giovanna, additional, and Brancati, Francesco, additional

Published
2014
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202. A spastic paraplegia mouse model reveals REEP1-dependent ER shaping

Author

Beetz, Christian, primary, Koch, Nicole, additional, Khundadze, Mukhran, additional, Zimmer, Geraldine, additional, Nietzsche, Sandor, additional, Hertel, Nicole, additional, Huebner, Antje-Kathrin, additional, Mumtaz, Rizwan, additional, Schweizer, Michaela, additional, Dirren, Elisabeth, additional, Karle, Kathrin N., additional, Irintchev, Andrey, additional, Alvarez, Victoria, additional, Redies, Christoph, additional, Westermann, Martin, additional, Kurth, Ingo, additional, Deufel, Thomas, additional, Kessels, Michael M., additional, Qualmann, Britta, additional, and Hübner, Christian A., additional

Published
2014
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203. CLCN7andTCIRG1Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals

Author

Barvencik, Florian, primary, Kurth, Ingo, additional, Koehne, Till, additional, Stauber, Tobias, additional, Zustin, Jozef, additional, Tsiakas, Konstantinos, additional, Ludwig, Carmen F, additional, Beil, F Timo, additional, Pestka, Jan M, additional, Hahn, Michael, additional, Santer, Rene, additional, Supanchart, Chayarop, additional, Kornak, Uwe, additional, Fattore, Andrea Del, additional, Jentsch, Thomas J, additional, Teti, Anna, additional, Schulz, Ansgar, additional, Schinke, Thorsten, additional, and Amling, Michael, additional

Published
2014
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204. Search for cis-acting factors and maternal effect variants in Silver-Russell patients with ICR1 hypomethylation and their mothers

Author

Soellner, Lukas, Kraft, Florian, Sauer, Sabrina, Begemann, Matthias, Kurth, Ingo, Elbracht, Miriam, and Eggermann, Thomas

Abstract

Silver-Russell syndrome is an imprinting disorder characterized by severe intrauterine and postnatal growth retardation. The majority of patients show loss of methylation (LOM) of the H19/IGF2 IG-DMR (ICR1) in 11p15.5. In ~10% of these patients aberrant methylation of additional imprinted loci on other chromosomes than 11 can be observed (multilocus imprinting defect – MLID). Recently, genomic variations in the ICR1 have been associated with disturbed methylation of the ICR1. In addition, variants in factors contributing to the life cycle of imprinting are discussed to cause aberrant imprinting, including MLID. These variants can either be identified in the patients with imprinting disorders themselves or in their mothers. We performed comprehensive studies to elucidate the role of both cis-acting variants in 11p15.5 as well as of maternal effect variants in the etiology of ICR1 LOM. Whereas copy number analysis and next generation sequencing in the ICR1 did not provide any evidence for a variant, search for maternal effect variants in 21 mothers of patients with ICR1 LOM identified two carriers of NLRP5variants. By considering our results as well as those from the literature, we conclude that the causes for epimutations are heterogeneous. MLID might be regarded as an own etiological subgroup, associated with maternal effect variants in NLRPand functionally related genes. In addition, these variants might also contribute to LOM of single imprinted loci. Furthermore, genomic variants in the patients themselves might result in aberrant methylation patterns and need further investigation.

Published
2019
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205. Untersuchungen zur Zytokinbindung und Rezeptoraktivierung des Signaltransduktors gp130 durch seine Liganden IL-6 und IL-11

Author

Kurth, Ingo and Heinrich, Peter C.

Subjects
Interleukin 11, Rezeptor, %22">Aktivierung , Zytokine, Immunologie, Medizin, Interleukin 6, ddc:610, Rezeptoren, Cytokine, Bindestelle
Abstract

The glycoprotein 130 (gp130) is expressed as a transmembrane receptor on the cellsurface of many cells. It acts as the central signal transducing subunit of the family of IL-6-type cytokines thereby initiating several biological responses. The aim of this work was to characterize the properties of ligand binding and activation of gp130 in detail: - Two different binding epitopes are required for ligand binding of the gp130 homodimerizing cytokines. One contact is provided by a region in the cytokine-binding module (CBM) of the receptor. The respective amino acids are in analogous position to the important residues within the CBM of the growth hormone receptor binding the growth hormone. The latter receptor belongs to a family of short-chain cytokine receptors. - A second contact region between gp130 and the homodimerizing ligands is provided by the Ig-like domain of the receptor thereby forming an asymmetrical dimer in complex with IL-6/IL-6R and IL-11/IL-11R. - The three membrane-proximal domains of gp130 (D4, D5 and D6) are responsible for the activation of the receptor. The deletion of D4 and D6 of gp130 leads to a partial loss of the cytokine binding affinity due to a conformational change. The deletion of D5 of gp130 does not influence the binding properties. - D4, D5 and D6 are all indispensable for receptor activation by cytokines. Cytokine independent activation by agonistic antibodies leads to partial activation of the receptor lacking domain 4 or 6. In contrast domain 5 is absolutely essential for the activation by these stimuli. - The important role of D5 of gp130 is also shown by replacing this domain with the analogous domain of the GCSFR. This chimeric receptor leads to a constitutively active receptor variant, highlighting this domain as important for receptor activation. - The results point towards a functional dichotomy of gp130 into a ligand binding and a receptor activating region.

Published
2003

206. Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita

Author

Kirschner, Martin, Maurer, Angela, Wlodarski, Marcin, Ventura Ferreira, Monica, Bouillon, Anne-Sophie, Halfmeyer, Insa, Blau, Wolfgang, Kreuter, Michael, Rosewich, Martin, Corbacioglu, Selim, Beck, Joachim, Schwarz, Michaela, Bittenbring, Jörg, Radsak, Markus, Wilk, Christian, Koschmieder, Steffen, Begemann, Matthias, Kurth, Ingo, Schemionek, Mirle, Brümmendorf, Tim, and Beier, Fabian

Abstract

Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23–60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically relevant MDS-related somatic variant. This incidence was dramatically lower than formerly described in acquired AA. Based on our data, we conclude that clonal evolution of subclones carrying MDS-related mutations is not the predominant mechanism for MDS/AML initiation in adult cryptic DKC patients.

Published
2018
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207. Noncoding copy-number variations are associated with congenital limb malformation

Author

Flöttmann, Ricarda, Kragesteen, Bjørt K, Geuer, Sinje, Socha, Magdalena, Allou, Lila, Sowińska-Seidler, Anna, Bosquillon de Jarcy, Laure, Wagner, Johannes, Jamsheer, Aleksander, Oehl-Jaschkowitz, Barbara, Wittler, Lars, de Silva, Deepthi, Kurth, Ingo, Maya, Idit, Santos-Simarro, Fernando, Hülsemann, Wiebke, Klopocki, Eva, Mountford, Roger, Fryer, Alan, Borck, Guntram, Horn, Denise, Lapunzina, Pablo, Wilson, Meredith, Mascrez, Bénédicte, Duboule, Denis, Mundlos, Stefan, and Spielmann, Malte

Abstract

PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)–based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.

Published
2018
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208. Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering

Author

Krols, Michiel, Detry, Sammy, Asselbergh, Bob, Almeida-Souza, Leonardo, Kremer, Anna, Lippens, Saskia, De Rycke, Riet, De Winter, Vicky, Müller, Franz-Josef, Kurth, Ingo, McMahon, Harvey T., Savvides, Savvas N., Timmerman, Vincent, and Janssens, Sophie

Abstract

The endoplasmic reticulum (ER) is a complex network of sheets and tubules that is continuously remodeled. The relevance of this membrane dynamics is underscored by the fact that mutations in atlastins (ATLs), the ER fusion proteins in mammals, cause neurodegeneration. How defects in this process disrupt neuronal homeostasis is unclear. Using electron microscopy (EM) volume reconstruction of transfected cells, neurons, and patient fibroblasts, we show that hereditary sensory and autonomic neuropathy (HSAN)-causing ATL3 mutants promote aberrant ER tethering hallmarked by bundles of laterally attached ER tubules. In vitro, these mutants cause excessive liposome tethering, recapitulating the results in cells. Moreover, ATL3 variants retain their dimerization-dependent GTPase activity but are unable to promote membrane fusion, suggesting a defect in an intermediate step of the ATL3 functional cycle. Our data show that the effects of ATL3 mutations on ER network organization go beyond a loss of fusion and shed light on neuropathies caused by atlastin defects.

Published
2018
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212. Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies

Author

Kim, Hyung-Goo, Kim, Hyun-Taek, Leach, Natalia T, Lan, Fei, Ullmann, Reinhard, Silahtaroglu, Asli, Kurth, Ingo, Nowka, Anja, Seong, Ihn Sik, Shen, Yiping, Talkowski, Michael E, Ruderfer, Douglas, Lee, Ji-Hyun, Glotzbach, Caron, Ha, Kyungsoo, Kjaergaard, Susanne, Levin, Alex V, Romeike, Bernd F, Kleefstra, Tjitske, Bartsch, Oliver, Elsea, Sarah H, Jabs, Ethylin Wang, MacDonald, Marcy E, Harris, David J, Quade, Bradley J, Ropers, Hans-Hilger, Shaffer, Lisa G, Kutsche, Kerstin, Layman, Lawrence C, Tommerup, Niels, Kalscheuer, Vera M, Shi, Yang, Morton, Cynthia C, Kim, Cheol-Hee, Gusella, James F, Kim, Hyung-Goo, Kim, Hyun-Taek, Leach, Natalia T, Lan, Fei, Ullmann, Reinhard, Silahtaroglu, Asli, Kurth, Ingo, Nowka, Anja, Seong, Ihn Sik, Shen, Yiping, Talkowski, Michael E, Ruderfer, Douglas, Lee, Ji-Hyun, Glotzbach, Caron, Ha, Kyungsoo, Kjaergaard, Susanne, Levin, Alex V, Romeike, Bernd F, Kleefstra, Tjitske, Bartsch, Oliver, Elsea, Sarah H, Jabs, Ethylin Wang, MacDonald, Marcy E, Harris, David J, Quade, Bradley J, Ropers, Hans-Hilger, Shaffer, Lisa G, Kutsche, Kerstin, Layman, Lawrence C, Tommerup, Niels, Kalscheuer, Vera M, Shi, Yang, Morton, Cynthia C, Kim, Cheol-Hee, and Gusella, James F

Abstract

Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for multiple exostoses and parietal foramina in PSS, the identity of the gene(s) associated with the ID and CFA phenotypes has remained elusive. Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription. In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation. Our finding that disruption of PHF21A by translocations in the PSS region is associated with ID adds to the growing list of ID-associated genes that emphasize the critical role of transcriptional regulation and chromatin remodeling in normal brain development and cognitive function.

Published
2012

214. A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal System

Author

Khundadze, Mukhran, primary, Kollmann, Katrin, additional, Koch, Nicole, additional, Biskup, Christoph, additional, Nietzsche, Sandor, additional, Zimmer, Geraldine, additional, Hennings, J. Christopher, additional, Huebner, Antje K., additional, Symmank, Judit, additional, Jahic, Amir, additional, Ilina, Elena I., additional, Karle, Kathrin, additional, Schöls, Ludger, additional, Kessels, Michael, additional, Braulke, Thomas, additional, Qualmann, Britta, additional, Kurth, Ingo, additional, Beetz, Christian, additional, and Hübner, Christian A., additional

Published
2013
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215. A spastic paraplegia mouse model reveals REEP1-dependent ER shaping

Author

Beetz, Christian, primary, Koch, Nicole, additional, Khundadze, Mukhran, additional, Zimmer, Geraldine, additional, Nietzsche, Sandor, additional, Hertel, Nicole, additional, Huebner, Antje-Kathrin, additional, Mumtaz, Rizwan, additional, Schweizer, Michaela, additional, Dirren, Elisabeth, additional, Karle, Kathrin N., additional, Irintchev, Andrey, additional, Alvarez, Victoria, additional, Redies, Christoph, additional, Westermann, Martin, additional, Kurth, Ingo, additional, Deufel, Thomas, additional, Kessels, Michael M., additional, Qualmann, Britta, additional, and Hübner, Christian A., additional

Published
2013
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216. A de novo gain-of-function mutation in SCN11A causes loss of pain perception

Author

Leipold, Enrico, primary, Liebmann, Lutz, additional, Korenke, G Christoph, additional, Heinrich, Theresa, additional, Gießelmann, Sebastian, additional, Baets, Jonathan, additional, Ebbinghaus, Matthias, additional, Goral, R Oliver, additional, Stödberg, Tommy, additional, Hennings, J Christopher, additional, Bergmann, Markus, additional, Altmüller, Janine, additional, Thiele, Holger, additional, Wetzel, Andrea, additional, Nürnberg, Peter, additional, Timmerman, Vincent, additional, De Jonghe, Peter, additional, Blum, Robert, additional, Schaible, Hans-Georg, additional, Weis, Joachim, additional, Heinemann, Stefan H, additional, Hübner, Christian A, additional, and Kurth, Ingo, additional

Published
2013
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217. Renal intercalated cells are rather energized by a proton than a sodium pump

Author

Chambrey, Régine, primary, Kurth, Ingo, additional, Peti-Peterdi, Janos, additional, Houillier, Pascal, additional, Purkerson, Jeffrey M., additional, Leviel, Françoise, additional, Hentschke, Moritz, additional, Zdebik, Anselm A., additional, Schwartz, George J., additional, Hübner, Christian A., additional, and Eladari, Dominique, additional

Published
2013
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218. Stroke-like onset of brain stem degeneration presents with unique MRI sign and heterozygous NMNAT2 variant:a case report.

Author

Schulz, Alexander, Wagner, Franziska, Ungelenk, Martin, Kurth, Ingo, and Redecker, Christoph

Subjects
BRAIN degeneration, BRAIN stem diseases, MAGNETIC resonance imaging
Abstract

Background: Acute-onset neurodegenerative diseases in older patients are rare clinical cases, especially when the degeneration only affects specific regions of the nervous system. Several neurological disorders have been described in which the degeneration of brain parenchyma originates from and/or primarily affects the brain stem. Clinical diagnosis in these patients, however, is often complicated due to a poor understanding of these diseases and their underlying mechanisms. Case presentation: In this manuscript we report on a 73-year-old female who had experienced a sudden onset of complex neurological symptoms that progressively worsened over a period of 2 years. Original evaluation had suggested a MRI-negative stroke as underlying pathogenesis. The combination of patient's medical history, clinical examination and exceptional pattern of brain stem degeneration presenting as "kissing swan sign" in MR imaging was strongly suggestive of acute onset of Alexander's disease. This leukoencephalopathy is caused by GFAP(glial fibrilary acidic protein) gene mutations and may present with brain stem atrophy and stroke-like onset of symptoms in elderly individuals. However, a pathognomonic GFAP gene mutation could not be identified by Sanger sequencing. Conclusions: After an extended differential diagnosis and exclusion of other diseases, a definite diagnosis of the patient's condition presently remains elusive. However, whole-exome sequencing performed from patient's blood revealed 12 potentially disease-causative heterozygous variants, amongst which several have been associated with neurological disorders in vitro and in vivo-in particular the axon degeneration-related NMNAT2 gene. [ABSTRACT FROM AUTHOR]

Published
2016
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221. Translocations Disrupting PHF21A in the Potocki-Shaffer-Syndrome Region Are Associated with Intellectual Disability and Craniofacial Anomalies

Author

Kim, Hyung-Goo, primary, Kim, Hyun-Taek, additional, Leach, Natalia T., additional, Lan, Fei, additional, Ullmann, Reinhard, additional, Silahtaroglu, Asli, additional, Kurth, Ingo, additional, Nowka, Anja, additional, Seong, Ihn Sik, additional, Shen, Yiping, additional, Talkowski, Michael E., additional, Ruderfer, Douglas, additional, Lee, Ji-Hyun, additional, Glotzbach, Caron, additional, Ha, Kyungsoo, additional, Kjaergaard, Susanne, additional, Levin, Alex V., additional, Romeike, Bernd F., additional, Kleefstra, Tjitske, additional, Bartsch, Oliver, additional, Elsea, Sarah H., additional, Jabs, Ethylin Wang, additional, MacDonald, Marcy E., additional, Harris, David J., additional, Quade, Bradley J., additional, Ropers, Hans-Hilger, additional, Shaffer, Lisa G., additional, Kutsche, Kerstin, additional, Layman, Lawrence C., additional, Tommerup, Niels, additional, Kalscheuer, Vera M., additional, Shi, Yang, additional, Morton, Cynthia C., additional, Kim, Cheol-Hee, additional, and Gusella, James F., additional

Published
2012
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223. Variant of the catalytic cysteine of UFSP2 leads to spondyloepimetaphyseal dysplasia type Di Rocco

Author

Mattern, Larissa, Begemann, Matthias, Delbrück, Heide, Holschbach, Petra, Schröder, Silvia, Schacht, Sabine M., Kurth, Ingo, and Elbracht, Miriam

Abstract

Spondyloepimetaphyseal dysplasia (SEMD) is characterized by vertebral, epiphyseal, and metaphyseal alterations. Patients become predominantly apparent with disproportionate short stature. The genetic background of SEMD is heterogeneous, with different modes of inheritance (autosomal dominant, autosomal recessive, and X-linked disorders). Amongst the genes in which variants are known to cause SEMD, UFM1-specific protease 2(UFSP2) encodes a cysteine protease involved in the maturation of Ubiquitin-fold modifier 1 (UFM1). Heterozygous pathogenic variants affecting the C-terminal catalytic domain of UFSP2 are related to two entities of skeletal dysplasia, Beukes hip dysplasia (BHD) and SEMD type Di Rocco (SEMDDR). This is the first report of a de novoheterozygous variant affecting the catalytic Cys302 residue of UFSP2(NM_018359.3:c.905G>C, p.(Cys302Ser)) causing SEMDDR. According to previously described patients with SEMDDR, our patient presented with disproportionate short stature, genu varum, gait instability, and radiologically detected epiphyseal and metaphyseal alterations. Additionally, a bell-shaped thorax, lumbar hyperlordosis, muscular hypotonia, and coxa vara were observed in the patient described in this study. Our findings underline the fundamental importance of an intact catalytic triad of the human UFSP2 for normal skeletal development and extend the phenotypical features of patients with UFSP2-related skeletal dysplasia.

Published
2023
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224. Duplications ofBHLHA9are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

Author

Klopocki, Eva, primary, Lohan, Silke, additional, Doelken, Sandra C, additional, Stricker, Sigmar, additional, Ockeloen, Charlotte W, additional, Soares Thiele de Aguiar, Renata, additional, Lezirovitz, Karina, additional, Mingroni Netto, Regina Celia, additional, Jamsheer, Aleksander, additional, Shah, Hitesh, additional, Kurth, Ingo, additional, Habenicht, Rolf, additional, Warman, Matthew, additional, Devriendt, Koenraad, additional, Kordaß, Ulrike, additional, Hempel, Maja, additional, Rajab, Anna, additional, Mäkitie, Outi, additional, Naveed, Mohammed, additional, Radhakrishna, Uppala, additional, Antonarakis, Stylianos E, additional, Horn, Denise, additional, and Mundlos, Stefan, additional

Published
2011
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226. Unique phenotype in a patient with CHARGE syndrome

Author

Jain, Shobhit, primary, Kim, Hyung-Goo, additional, Lacbawan, Felicitas, additional, Meliciani, Irene, additional, Wenzel, Wolfgang, additional, Kurth, Ingo, additional, Sharma, Josefina, additional, Schoeneman, Morris, additional, Ten, Svetlana, additional, Layman, Lawrence C, additional, and Jacobson-Dickman, Elka, additional

Published
2011
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227. The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice

Author

Leviel, Françoise, primary, Hübner, Christian A., additional, Houillier, Pascal, additional, Morla, Luciana, additional, El Moghrabi, Soumaya, additional, Brideau, Gaëlle, additional, Hassan, Hatim, additional, Parker, Mark D., additional, Kurth, Ingo, additional, Kougioumtzes, Alexandra, additional, Sinning, Anne, additional, Pech, Vladimir, additional, Riemondy, Kent A., additional, Miller, R. Lance, additional, Hummler, Edith, additional, Shull, Gary E., additional, Aronson, Peter S., additional, Doucet, Alain, additional, Wall, Susan M., additional, Chambrey, Régine, additional, and Eladari, Dominique, additional

Published
2011
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228. WDR11, a WD Protein that Interacts with Transcription Factor EMX1, Is Mutated in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome

Author

Kim, Hyung-Goo, primary, Ahn, Jang-Won, additional, Kurth, Ingo, additional, Ullmann, Reinhard, additional, Kim, Hyun-Taek, additional, Kulharya, Anita, additional, Ha, Kyung-Soo, additional, Itokawa, Yasuhide, additional, Meliciani, Irene, additional, Wenzel, Wolfgang, additional, Lee, Deresa, additional, Rosenberger, Georg, additional, Ozata, Metin, additional, Bick, David P., additional, Sherins, Richard J., additional, Nagase, Takahiro, additional, Tekin, Mustafa, additional, Kim, Soo-Hyun, additional, Kim, Cheol-Hee, additional, Ropers, Hans-Hilger, additional, Gusella, James F., additional, Kalscheuer, Vera, additional, Choi, Cheol Yong, additional, and Layman, Lawrence C., additional

Published
2010
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229. Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy

Author

Kurth, Ingo, primary, Pamminger, Torsten, additional, Hennings, J Christopher, additional, Soehendra, Désirée, additional, Huebner, Antje K, additional, Rotthier, Annelies, additional, Baets, Jonathan, additional, Senderek, Jan, additional, Topaloglu, Haluk, additional, Farrell, Sandra A, additional, Nürnberg, Gudrun, additional, Nürnberg, Peter, additional, De Jonghe, Peter, additional, Gal, Andreas, additional, Kaether, Christoph, additional, Timmerman, Vincent, additional, and Hübner, Christian A, additional

Published
2009
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230. Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina

Author

Chrispell, Jared D., primary, Feathers, Kecia L., additional, Kane, Maureen A., additional, Kim, Chul Y., additional, Brooks, Matthew, additional, Khanna, Ritu, additional, Kurth, Ingo, additional, Hübner, Christian A., additional, Gal, Andreas, additional, Mears, Alan J., additional, Swaroop, Anand, additional, Napoli, Joseph L., additional, Sparrow, Janet R., additional, and Thompson, Debra A., additional

Published
2009
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231. Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia

Author

Kurth, Ingo, primary, Klopocki, Eva, additional, Stricker, Sigmar, additional, van Oosterwijk, Jolieke, additional, Vanek, Sebastian, additional, Altmann, Jens, additional, Santos, Heliosa G, additional, van Harssel, Jeske J T, additional, de Ravel, Thomy, additional, Wilkie, Andrew O M, additional, Gal, Andreas, additional, and Mundlos, Stefan, additional

Published
2009
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232. Analysis of Rare APC Variants at the mRNA Level

Author

Kaufmann, Astrid, primary, Vogt, Stefanie, additional, Uhlhaas, Siegfried, additional, Stienen, Dietlinde, additional, Kurth, Ingo, additional, Hameister, Horst, additional, Mangold, Elisabeth, additional, Kötting, Judith, additional, Kaminsky, Elke, additional, Propping, Peter, additional, Friedl, Waltraut, additional, and Aretz, Stefan, additional

Published
2009
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233. Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability

Author

Jacobs, Stefan, primary, Ruusuvuori, Eva, additional, Sipilä, Sampsa T., additional, Haapanen, Aleksi, additional, Damkier, Helle H., additional, Kurth, Ingo, additional, Hentschke, Moritz, additional, Schweizer, Michaela, additional, Rudhard, York, additional, Laatikainen, Linda M., additional, Tyynelä, Jaana, additional, Praetorius, Jeppe, additional, Voipio, Juha, additional, and Hübner, Christian A., additional

Published
2008
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235. Regulation of endoplasmic reticulum turnover by selective autophagy.

Author

Khaminets, Aliaksandr, Heinrich, Theresa, Mari, Muriel, Grumati, Paolo, Huebner, Antje K., Akutsu, Masato, Liebmann, Lutz, Stolz, Alexandra, Nietzsche, Sandor, Koch, Nicole, Mauthe, Mario, Katona, Istvan, Qualmann, Britta, Weis, Joachim, Reggiori, Fulvio, Kurth, Ingo, Hübner, Christian A., and Dikic, Ivan

Subjects
ENDOPLASMIC reticulum, INTRACELLULAR membranes, LIPID synthesis, HOMEOSTASIS, AUTOPHAGY, NEUROPATHY
Abstract

The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans. [ABSTRACT FROM AUTHOR]

Published
2015
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241. CLCN7 and TCIRG1 Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals.

Author

Barvencik, Florian, Kurth, Ingo, Koehne, Till, Stauber, Tobias, Zustin, Jozef, Tsiakas, Konstantinos, Ludwig, Carmen F, Beil, F Timo, Pestka, Jan M, Hahn, Michael, Santer, Rene, Supanchart, Chayarop, Kornak, Uwe, Fattore, Andrea Del, Jentsch, Thomas J, Teti, Anna, Schulz, Ansgar, Schinke, Thorsten, and Amling, Michael

Abstract

ABSTRACT Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl−/H+ exchanger CLC-7 and the a3 subunit of the vacuolar H+-ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc/ oc mice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A ( n = 1), CLCN7 ( n = 3), or TCIRG1 ( n = 3). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A-dependent or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2014
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243. Severe case and literature review of primary erythromelalgia: Novel SCN9A gene mutation.

Author

Skeik, Nedaa, Rooke, Thom W, Davis, Mark Denis P, Davis, Dawn Marie R, Kalsi, Henna, Kurth, Ingo, and Richardson, Randal C

Subjects
ERYTHROMELALGIA, LEG diseases, SENSORY neurons, ERYTHEMA, HYPOTHYROIDISM diagnosis, SOMATOMEDIN, PATIENTS, PHYSIOLOGY
Abstract

Erythromelalgia is a rare clinical syndrome characterized by intermittent heat, redness, swelling and pain more commonly affecting the lower extremities. Symptoms are mostly aggravated by warmth and are eased by a cold temperature. In some cases, symptoms can be very severe and disabling. Erythromelalgia can be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Recently, there has been a lot of progress in studying Na(v)1.7 sodium channels (expressed mostly in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion) and different mutations affecting the encoding SCN9A gene that leads to channelopathies responsible for some disorders, including primary erythromelalgia. We present a severe case of progressive primary erythromelalgia caused by a new de novo heterozygous missense mutation (c.2623C>G) of the SCN9A gene which substitutes glutamine 875 by glutamic acid (p.Q875E). To our knowledge, this mutation has not been previously reported in the literature. We also provided a short literature review about erythromelalgia and Na(v) sodium channelopathies. [ABSTRACT FROM AUTHOR]

Published
2012
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244. Mice with a Targeted Disruption of the Cl-/HCO3 Exchanger AE3 Display a Reduced Seizure Threshold.

Author

Hentschke, Moritz, Wiemann, Martin, Hentschke, Suna, Kurth, Ingo, Hermans-Borgmeyer, Irm, Seidenbecher, Thomas, Jentsch, Thomas J., Gal, Andreas, and Hübner, Christian A.

Subjects
NEURONS, ASTROCYTES, NEUROGLIA, HYDROGEN-ion concentration, SODIUM, EPILEPSY, CELLS
Abstract

Neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH. The sodium-independent electroneutral anion exchangers (AEs) exchange intracellular bicarbonate for extracellular chloride and thereby lower the intracellular pH. Recently, a significant association was found with the variant Ala867Asp of the anion exchanger AE3, which is predominantly expressed in brain and heart, in a large cohort of patients with idiopathic generalized epilepsy. To analyze a possible involvement of AE3 dysfunction in the pathogenesis of seizures, we generated an AE3-knockout mouse model by targeted disruption of Slc4a3. AE3-knockout mice were apparently healthy, and neither displayed gross histological and behavioral abnormalities nor spontaneous seizures or spike wave complexes in electrocorticograms. However, the seizure threshold of AE3-knockout mice exposed to bicuculline, pentylenetetrazole, or pilocarpine was reduced, and seizure-induced mortality was significantly increased compared to wild-type littermates. In the pyramidal cell layer of the hippocampal CA3 region, where AE3 is strongly expressed, disruption of AE3 abolished sodium-independent chloride-bicarbonate exchange. These findings strongly support the hypothesis that AE3 modulates seizure susceptibility and, therefore, are of significance for understanding the role of intracellular pH in epilepsy. [ABSTRACT FROM AUTHOR]

Published
2006
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245. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P.

Author

Woods, Christopher Geoffrey, Babiker, Mohamed Osman Eltahir, Horrocks, Iain, Tolmie, John, and Kurth, Ingo

Subjects
DIFFERENTIAL diagnosis, CONGENITAL insensitivity to pain, PAIN perception
Abstract

A letter to the editor is presented in response to the article "The differential diagnosis of congenital analgesia and other diseases with diminished pain perception in childhood. Case report and review" by W. Görke in the previous issue.

Published
2015
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246. CNVizard—a lightweight streamlit application for an interactive analysis of copy number variants.

Author

Krause, Jeremias, Classen, Carlos, Dey, Daniela, Lausberg, Eva, Kessler, Luise, Eggermann, Thomas, Kurth, Ingo, Begemann, Matthias, and Kraft, Florian

Subjects
*DNA copy number variations, *GENETIC testing, *DATA visualization, *DATA analysis, *ANNOTATIONS
Abstract

Background: Methods to call, analyze and visualize copy number variations (CNVs) from massive parallel sequencing data have been widely adopted in clinical practice and genetic research. To enable a streamlined analysis of CNV data, comprehensive annotations and good visualizations are indispensable. The ability to detect single exon CNVs is another important feature for genetic testing. Nonetheless, most available open-source tools come with limitations in at least one of these areas. One additional drawback is that available tools deliver data in an unstructured and static format which requires subsequent visualization and formatting efforts. Results: Here we present CNVizard, an interactive Streamlit app allowing a comprehensive visualization of CNVkit data. Furthermore, combining CNVizard with the CNVand pipeline allows the annotation and visualization of CNV or SV VCF files from any CNV caller. Conclusion: CNVizard, in combination with CNVand, enables the comprehensive and streamlined analysis of short- and long-read sequencing data and provide an intuitive webapp-like experience enabling an interactive visualization of CNV data. [ABSTRACT FROM AUTHOR]

Published
2024
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247. Diagnostic Use of Genome Sequencing in Patients With 11p15.5 Imprinting Disorder Features: A Pilot Study.

Author

Kessler, Luise, Krause, Jeremias, Kraft, Florian, Amin, Asmaa K., Fekete, Gyorgy, Lengyel, Anna, Pinti, Eva, Kovacs, Arpad, Lischka, Annette, Eggermann, Katja, Kurth, Ingo, Knopp, Cordula, Elbracht, Miriam, Begemann, Matthias, and Eggermann, Thomas

Subjects
*NUCLEOTIDE sequencing, *GENETIC disorder diagnosis, *MOLECULAR diagnosis, *PILOT projects, *HETEROGENEITY
Abstract

ABSTRACT To assess the suitability of genome sequencing (GS) as the second step in the diagnostics of patients with the features of 11p15.5‐associated imprinting disorders (ImpDis: Silver–Russell syndrome [SRS], Beckwith–Wiedemann syndrome [BWS]), we performed short‐read GS in patients negatively tested for imprinting disturbances. Obtaining a genetic diagnosis for patients with the features of these syndromes is challenging due to the clinical and molecular heterogeneity and overlap, and many patients remain undiagnosed after the currently suggested stepwise diagnostic workup. GS was conducted in 48 patients (SRS features: n = 37 and BWS features: n = 11). The detection rate differed markedly between the ImpDis: although a genetic cause could be identified in 51% of patients referred with SRS features, no pathogenic variants were detected in patients with BWS features. Thus, GS substantially improves the diagnostic yield and broadens the spectrum of overlapping disorders with SRS features. Obtaining a precise molecular diagnosis provides the basis for a personalized clinical management. Our findings support the use of GS as a second‐tier diagnostic tool for patients with growth disturbances, as it addresses all currently known variant types and shortens the diagnostic odyssey. [ABSTRACT FROM AUTHOR]

Published
2024
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248. Analysis of Rare APCVariants at the mRNA Level

Author

Kaufmann, Astrid, Vogt, Stefanie, Uhlhaas, Siegfried, Stienen, Dietlinde, Kurth, Ingo, Hameister, Horst, Mangold, Elisabeth, Kötting, Judith, Kaminsky, Elke, Propping, Peter, Friedl, Waltraut, and Aretz, Stefan

Abstract

In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APCvariants in patients with familial adenomatous polyposis at the mRNA level. APCvariants c.531 + 5GC and c.532-8GA in intron 4, c.1409-2_1409delAGG in intron 10, c.1548GA in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742AG leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548GA was detected in the index patient but not in his affected father, suggesting mutational mosaicism. A literature review shows that most of the rare APCvariants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APCvariants, particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms, and could lead to better treatment modalities.

Published
2009
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249. The forkhead transcription factor Foxi1 directly activates the AE4 promoter

Author

Kurth, Ingo, Hentschke, Moritz, Hentschke, Suna, Borgmeyer, Uwe, Gal, Andreas, and Hübner, Christian A.

Abstract

Intercalated cells are highly specialized cells within the renal collecting duct epithelium and play an important role in systemic acid–base homoeostasis. Whereas type A intercalated cells secrete protons via an apically localized H+-ATPase, type B intercalated cells secrete HCO3−. Type B intercalated cells specifically express the HCO3−/Cl− exchanger AE4 (anion exchanger 4), encoded by Slc4a9. Mice with a targeted disruption of the gene for the forkhead transcription factor Foxi1 display renal tubular acidosis due to an intercalated cell-differentiation defect. Collecting duct cells in these mice are characterized by the absence of inter-calated cell markers including AE4. To test whether Slc4a9 is a direct target gene of Foxi1, an AE4 promoter construct was generated for a cell-based reporter gene assay. Co-transfection with the Foxi1 cDNA resulted in an approx. 100-fold activation of the AE4 promoter construct. By truncating the AE4 promoter at the 5′-end, we demonstrate that a fragment of approx. 462 bp upstream of the transcription start point is sufficient to mediate activation by Foxi1. Sequence analysis of this region revealed at least eight potential binding sites for Foxi1 in both sense and antisense orientation. Only one element was bound by recombinant Foxi1 protein in bandshift assays. Mutation of this site abolished both binding in bandshift assays and transcriptional activation by co-transfection of Foxi1 in the reporter gene assay. We thus identify the AE4 promoter as a direct target of Foxi1.

Published
2006
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250. Clinical Presentation of Patients with Adult Late-Onset Telomere Biology Disorders - Results from the Aachen Telomeropathy Registry

Author

Beier, Fabian, Tometten, Mareike, Kirschner, Martin, Halfmeyer, Insa, Vieri, Margherita, Kricheldorf, Kim, Maurer, Angela, Roeth, Alexander, Platzbecker, Uwe, Radsak, Markus P., Schafhausen, Philippe, Corbacioglu, Selim, Hoechsmann, Britta, Wilk, C. Matthias, Hinze, Claas, Chromik, Jörg, Egle, Alexander, Heuser, Michael, Kreuter, Michael, Kurth, Ingo, Koschmieder, Steffen, Panse, Jens, Meyer, Robert, Isfort, Susanne, and Brummendorf, Tim H

Abstract

Introduction:Telomere biology disorders (TBD) are caused by mutations affecting proper telomere maintenance resulting in premature telomere shortening. Telomere length (TL) assessment is currently being used for screening and diagnosis of TBD of which Dyskeratosis congenita (DKC) is the most prominent TBD subtype typically found in children and adolescents. In adults, TBDs are characterized by a broad spectrum of more “cryptic” diverging mono- or oligosymptomatic clinical manifestations such as bone marrow failure (BMF), hepatopathy or interstitial lung disease (ILD). However, despite growing general clinical awareness and exertion of improved TL screening strategies, insufficient data are available about the clinical course of adult, late-onset TBDs. Here, we present a series of 41 consecutive adult TBD cases from 2014 to 2021 identified through the Aachen Telomeropathy registry.

Published
2021
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