151 results on '"Lausch E"'
Search Results
2. Genetische Formen des Kleinwuchses und neue Behandlungskonzepte
- Author
-
Zabel, B. and Lausch, E.
- Published
- 2014
- Full Text
- View/download PDF
3. Therapie genetisch bedingter Krankheiten
- Author
-
Lausch, E., primary and Spranger, J., additional
- Published
- 2015
- Full Text
- View/download PDF
4. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family
- Author
-
Dai, J, Kim, O-H, Cho, T-J, Schmidt-Rimpler, M, Tonoki, H, Takikawa, K, Haga, N, Miyoshi, K, Kitoh, H, Yoo, W-J, Choi, I-H, Song, H-R, Jin, D-K, Kim, H-T, Kamasaki, H, Bianchi, P, Grigelioniene, G, Nampoothiri, S, Minagawa, M, Miyagawa, S-i, Fukao, T, Marcelis, C, Jansweijer, M C E, Hennekam, R C M, Bedeschi, F, Mustonen, A, Jiang, Q, Ohashi, H, Furuichi, T, Unger, S, Zabel, B, Lausch, E, Superti-Furga, A, Nishimura, G, and Ikegawa, S
- Published
- 2010
- Full Text
- View/download PDF
5. Severe Osteogenesis imperfecta with oligodontia: think of MESD
- Author
-
Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C. A., Cabral de Menezes, H., Lausch, E., Lorini, P. V., Lamounier, A., Jr., Carniero, T. C. B., Giunta, C., Rohrbach, M., Janner, M., Semler, O., Beleggia, F., Li, Y., Yigit, G., Reintjes, N., Altmuller, J., Nurnberg, P., Cavalcanti, D. P., Zabel, B., Warman, M. L., Bertola, D. R., Wollnik, B., Netzer, C., Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C. A., Cabral de Menezes, H., Lausch, E., Lorini, P. V., Lamounier, A., Jr., Carniero, T. C. B., Giunta, C., Rohrbach, M., Janner, M., Semler, O., Beleggia, F., Li, Y., Yigit, G., Reintjes, N., Altmuller, J., Nurnberg, P., Cavalcanti, D. P., Zabel, B., Warman, M. L., Bertola, D. R., Wollnik, B., and Netzer, C.
- Published
- 2020
6. Loss of Functional Osteoprotegerin : More than a Skeletal Problem
- Author
-
Grasemann, Corinna, Unger, Nicole, Hovel, M., Arweiler-Harbeck, Diana, Lausch, E., Meissner, T., Hauffa, Berthold, and Shaw, N.
- Subjects
Medizin - Published
- 2016
7. Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening
- Author
-
Grünert, Sarah C., Wehrle, A., Villavicencio-Lorini, P., Lausch, E., Vetter, B., Schwab, K. O., Tucci, S., and Spiekerkoetter, U.
- Subjects
Newborn screening ,False negative ,Siblings ,DNA Mutational Analysis ,Missplicing ,Infant, Newborn ,Mutation, Missense ,Case Report ,Polymorphism, Single Nucleotide ,Acyl-CoA Dehydrogenase ,Lipid Metabolism, Inborn Errors ,Pedigree ,Neonatal Screening ,Germany ,Genetics ,Humans ,Protein Isoforms ,Genetics(clinical) ,Female ,ACADM ,DNA Primers - Abstract
Background Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial fatty acid β-oxidation and a target disease of newborn screening in many countries. Case presentation We report on two siblings with mild MCAD deficiency associated with a novel splice site mutation in the ACADM gene. The younger sibling was detected by newborn screening, while the older sister was missed, but diagnosed later on by genetic family testing. Both children were found to be compound heterozygous for the common c.985A > G (p.K329E) mutation and a novel splice site mutation, c.600-18G > A, in the ACADM gene. To determine the biological consequence of the c.600-18G > A mutation putative missplicing was investigated at RNA level in granulocytes and monocytes of one of the patients. The splice site mutation was shown to lead to partial missplicing of the ACADM pre-mRNA. Of three detected transcripts two result in truncated, non-functional MCAD proteins as reflected by the reduced octanoyl-CoA oxidation rate in both patients. In one patient a decrease of the octanoyl-CoA oxidation rate was found during a febrile infection indicating that missplicing may be temperature-sensitive. Conclusions Our data indicate that the c.600-18G > A variant activates a cryptic splice site, which competes with the natural splice site. Due to only partial missplicing sufficient functional MCAD protein remains to result in mild MCADD that may be missed by newborn screening. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0199-5) contains supplementary material, which is available to authorized users.
- Published
- 2015
8. Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation
- Author
-
Steinbusch, M.M.F., Caron, M.M.J., Surtel, D.A.M., Friedrich, F., Lausch, E., Pruijn, G., Verhesen, W., Schroen, B.L.M., van Rhijn, L.W., Zabel, B., Welting, T.J.M., Steinbusch, M.M.F., Caron, M.M.J., Surtel, D.A.M., Friedrich, F., Lausch, E., Pruijn, G., Verhesen, W., Schroen, B.L.M., van Rhijn, L.W., Zabel, B., and Welting, T.J.M.
- Abstract
Contains fulltext : 177137.pdf (publisher's version ) (Open Access)
- Published
- 2017
9. Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with 'Corner Fractures'
- Author
-
Lee, C.S., Fu, H., Baratang, N., Rousseau, J., Kumra, H., Sutton, V.R., Niceta, M., Ciolfi, A., Yamamoto, G., Bertola, D., Marcelis, C.L., Lugtenberg, D., Bartuli, A., Kim, C., Hoover-Fong, J., Sobreira, N., Pauli, R., Bacino, C., Krakow, D., Parboosingh, J., Yap, P., Kariminejad, A., McDonald, M.T., Aracena, M.I., Lausch, E., Unger, S., Superti-Furga, A., Lu, J.T., Cohn, D.H., Tartaglia, M., Lee, B.H., Reinhardt, D.P., Campeau, P.M., Lee, C.S., Fu, H., Baratang, N., Rousseau, J., Kumra, H., Sutton, V.R., Niceta, M., Ciolfi, A., Yamamoto, G., Bertola, D., Marcelis, C.L., Lugtenberg, D., Bartuli, A., Kim, C., Hoover-Fong, J., Sobreira, N., Pauli, R., Bacino, C., Krakow, D., Parboosingh, J., Yap, P., Kariminejad, A., McDonald, M.T., Aracena, M.I., Lausch, E., Unger, S., Superti-Furga, A., Lu, J.T., Cohn, D.H., Tartaglia, M., Lee, B.H., Reinhardt, D.P., and Campeau, P.M.
- Abstract
Item does not contain fulltext, Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
- Published
- 2017
10. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies
- Author
-
Shaheen, R., Schmidts, M., Faqeih, E., Hashem, A., Lausch, E., Holder, I., Superti-Furga, A., Mitchison, H.M., Almoisheer, A., Alamro, R., Alshiddi, T., Alzahrani, F., Beales, P.L., Alkuraya, F.S., and UK10K Consortium
- Subjects
Male ,Ellis-Van Creveld Syndrome ,Molecular Sequence Data ,Mutation, Missense ,Saudi Arabia ,Cell Cycle Proteins ,Bone and Bones ,Cohort Studies ,Animals ,Humans ,Amino Acid Sequence ,Cilia ,Zebrafish ,Centrioles ,Chromosome Mapping ,Infant ,Articles ,Fibroblasts ,Magnetic Resonance Imaging ,Pedigree ,Europe ,Disease Models, Animal ,Phenotype ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Genetic Loci ,Chromosomes, Human, Pair 5 ,Female ,Genome-Wide Association Study - Abstract
Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies.
- Published
- 2015
11. Hereditäre Skeletterkrankungen unter besonderer Berücksichtigung der Gruppe genetisch entzündlicher/rheumatoider Osteoarthropathien
- Author
-
Zabel, B., additional, Lausch, E., additional, Matysiak, U., additional, and Mohnike, K., additional
- Published
- 2016
- Full Text
- View/download PDF
12. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement
- Author
-
Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., UK10K, Knoers, N.V., Roepman, R., Mitchison, H.M., Schmidts, Miriam, Arts, Heleen H., Bongers, Ernie M. H. F., Yap, Zhimin, Oud, Machteld M., Antony, Dinu, Duijkers, Lonneke, Emes, Richard D., Stalker, Jim, Yntema, Jan-Bart L., Plagnol, Vincent, Hoischen, Alexander, Gilissen, Christian, Forsythe, Elisabeth, Lausch, Ekkehart, Veltman, Joris A., Roeleveld, Nel, Superti-Furga, Andrea, Kutkowska-Kazmierczak, Anna, Kamsteeg, Erik-Jan, Elcioglu, Nursel, van Maarle, Merel C., Graul-Neumann, Luitgard M., Devriendt, Koenraad, Smithson, Sarah F., Wellesley, Diana, Verbeek, Nienke E., Hennekam, Raoul C. M., Kayserili, Hulya, Scambler, Peter J., Beales, Philip L., Knoers, Nine V. A. M., Roepman, Ronald, Mitchison, Hannah M., Human Genetics, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and UK10K
- Subjects
Exome/genetics ,Cytoplasmic Dyneins ,Models, Molecular ,Genetics and epigenetic pathways of disease [NCMLS 6] ,Protein Conformation ,Bioinformatics ,medicine.disease_cause ,0302 clinical medicine ,Models ,Genetic Screening/Counselling ,Missense mutation ,Developmental ,Exome ,CRYSTAL-STRUCTURE ,Diagnostics ,Genetics (clinical) ,Exome sequencing ,Renal disorder [IGMD 9] ,Genetics ,Microscopy ,0303 health sciences ,Mutation ,Polydactyly ,Developmental Defects ,DEFECTS ,Polymorphism, Single Nucleotide/genetics ,3. Good health ,Gene Components ,Ellis-Van Creveld Syndrome/genetics ,PELVIC-PHALANGEAL DYSTROPHY ,Single Nucleotide/genetics ,Sequence Analysis ,Mutation/genetics ,Ellis-Van Creveld Syndrome ,Molecular Sequence Data ,IFT ,Biology ,DYNEIN MOTOR DOMAIN ,Polymorphism, Single Nucleotide ,Fluorescence ,Frameshift mutation ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Molecular Genetics ,03 medical and health sciences ,Intraflagellar transport ,CYTOPLASMIC DYNEIN ,medicine ,RETROGRADE INTRAFLAGELLAR TRANSPORT ,Humans ,Polymorphism ,030304 developmental biology ,Clinical Genetics ,Base Sequence ,Genetic heterogeneity ,Molecular ,DNA ,Sequence Analysis, DNA ,Human Reproducion Genomic disorders and inherited multi-system disorders [NCEBP 12] ,medicine.disease ,LIGHT INTERMEDIATE CHAIN ,Microscopy, Fluorescence ,Cytoplasmic Dyneins/chemistry ,Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6] ,PRIMARY CILIARY DYSKINESIA ,Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] ,CAENORHABDITIS-ELEGANS ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 116495.pdf (Publisher’s version ) (Open Access) BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes. 15 p.
- Published
- 2013
13. Synchron rekurrierende Late-onset-Sepsis durch Gruppe B-Streptokokken bei Zwillingsfrühgeborenen
- Author
-
Elling, R., Hufnagel, M., De Zoysa, A., Lander, F., Lausch, E., Zumstein, K., Imm, A., Krueger, M., and Henneke, P.
- Subjects
ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Einleitung und Fragestellung: Gruppe B-Streptokokken (GBS) gehören weltweit zu den häufigsten Erregern der Neugeborenen-Sepsis. Während die Pathogenese der Early-onset-Sepsis gut verstanden ist und mit der intrapartalen antimikrobiellen Prophylaxe eine effektive Risikoreduktion erreicht[for full text, please go to the a.m. URL], 21. Jahrestagung der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI)
- Published
- 2013
14. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies.
- Author
-
UK10K Consortium, Shaheen, R., Schmidts, M., Faqeih, E., Hashem, A., Lausch, E., Holder, I., Superti-Furga, A., Mitchison, H.M., Almoisheer, A., Alamro, R., Alshiddi, T., Alzahrani, F., Beales, P.L., Alkuraya, F.S., UK10K Consortium, Shaheen, R., Schmidts, M., Faqeih, E., Hashem, A., Lausch, E., Holder, I., Superti-Furga, A., Mitchison, H.M., Almoisheer, A., Alamro, R., Alshiddi, T., Alzahrani, F., Beales, P.L., and Alkuraya, F.S.
- Abstract
Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies.
- Published
- 2015
15. Viperin; A novel chondrogenic regulator
- Author
-
Steinbusch, M.M., primary, Caron, M.M., additional, Eckmann, F., additional, Lausch, E., additional, van Rhijn, L.W., additional, Zabel, B., additional, and Welting, T.J., additional
- Published
- 2015
- Full Text
- View/download PDF
16. FAMILIAL MEDITERRANEAN FEVER AS AN UNUSUAL CAUSE OF ACUTE SCROTUM
- Author
-
LAUSCH, E., FISCH, M., and BEETZ, R.
- Published
- 2001
- Full Text
- View/download PDF
17. Transcriptional Regulation of the non-coding snorna RMRP during chondrogenic differentiation; a role for NFкB/P65?
- Author
-
Steinbusch, M.M., primary, Caron, M.M., additional, Eckmann, F., additional, Lausch, E., additional, van Rhijn, L.W., additional, Zabel, B., additional, and Welting, T.J., additional
- Published
- 2014
- Full Text
- View/download PDF
18. RNase MRP is a novel regulator of endochondral ossification
- Author
-
Caron, M.M., Steinbusch, M., Reicherter, K., Mattijssen, S., Surtel, D.A., Rhijn, L.W. van, Pruijn, G.J.M., Lausch, E., Zabel, B., Welting, T.J., Caron, M.M., Steinbusch, M., Reicherter, K., Mattijssen, S., Surtel, D.A., Rhijn, L.W. van, Pruijn, G.J.M., Lausch, E., Zabel, B., and Welting, T.J.
- Abstract
Item does not contain fulltext
- Published
- 2013
19. Synchron rekurrierende Late-onset-Sepsis durch Gruppe B-Streptokokken bei Zwillingsfrühgeborenen
- Author
-
Elling, R, Hufnagel, M, de Zoysa, A, Lander, F, Lausch, E, Zumstein, K, Imm, A, Krueger, M, Henneke, P, Elling, R, Hufnagel, M, de Zoysa, A, Lander, F, Lausch, E, Zumstein, K, Imm, A, Krueger, M, and Henneke, P
- Published
- 2013
20. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.
- Author
-
UK10K, Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R., Mitchison, H.M., UK10K, Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R., and Mitchison, H.M.
- Abstract
BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.
- Published
- 2013
21. Mutations in WNT1 cause different forms of bone fragility
- Author
-
Keupp, K., Beleggia, F., Kayserili, H., Barnes, A., Steiner, M., Semler, O., Fischer, B., Yigit, G., Janda, C., Becker, J., Breer, S., Altunoglu, U., Grünhagen, J., Krawitz, P., Hecht, J., Schinke, T., Makareeva, E., Lausch, E., Cankaya, T., Caparrós-Martín, Jose, Lapunzina, P., Temtamy, S., Aglan, M., Zabel, B., Eysel, P., Koerber, F., Leikin, S., Garcia, K., Netzer, C., Schönau, E., Ruiz-Perez, V., Mundlos, S., Amling, M., Kornak, U., Marini, J., Wollnik, B., Keupp, K., Beleggia, F., Kayserili, H., Barnes, A., Steiner, M., Semler, O., Fischer, B., Yigit, G., Janda, C., Becker, J., Breer, S., Altunoglu, U., Grünhagen, J., Krawitz, P., Hecht, J., Schinke, T., Makareeva, E., Lausch, E., Cankaya, T., Caparrós-Martín, Jose, Lapunzina, P., Temtamy, S., Aglan, M., Zabel, B., Eysel, P., Koerber, F., Leikin, S., Garcia, K., Netzer, C., Schönau, E., Ruiz-Perez, V., Mundlos, S., Amling, M., Kornak, U., Marini, J., and Wollnik, B.
- Abstract
We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis. © 2013 The American Society of Human Genetics.
- Published
- 2013
22. Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP
- Author
-
Vissers, L.E.L.M., Lausch, E., Unger, S., Campos-Xavier, A.B., Gilissen, C.F.H.A., Rossi, A. de, Rosario, M. del, Venselaar, H., Knoll, U., Nampoothiri, S., Nair, M., Spranger, J., Brunner, H.G., Bonafe, L., Veltman, J.A., Zabel, B., Superti-Furga, A., Vissers, L.E.L.M., Lausch, E., Unger, S., Campos-Xavier, A.B., Gilissen, C.F.H.A., Rossi, A. de, Rosario, M. del, Venselaar, H., Knoll, U., Nampoothiri, S., Nair, M., Spranger, J., Brunner, H.G., Bonafe, L., Veltman, J.A., Zabel, B., and Superti-Furga, A.
- Abstract
Item does not contain fulltext, We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.
- Published
- 2011
23. PReS-FINAL-2275: Improvement of calcinosis cutis with intravenous pamidronate in a 2-year-old girl with progressive widespread skin calcification of unknown origin
- Author
-
Mrusek, S, primary, Jeibmann, A, additional, Lausch, E, additional, and Ganser, G, additional
- Published
- 2013
- Full Text
- View/download PDF
24. RNase MRP is a novel regulator of endochondral ossification
- Author
-
Caron, M.M., primary, Steinbusch, M., additional, Reicherter, K., additional, Mattijssen, S., additional, Surtel, D.A., additional, van Rhijn, L.W., additional, Pruijn, G.J., additional, Lausch, E., additional, Zabel, B., additional, and Welting, T.J., additional
- Published
- 2013
- Full Text
- View/download PDF
25. Effekte von Lovastatin auf kortikaler und Amygdala-abhängiger synaptischer Plastizität im BDNF Val/Met Genotyp
- Author
-
Mainberger, F, primary, Nissen, C, additional, Holz, J, additional, Jung, N, additional, Langer, S, additional, Schnekenbühl, S, additional, Gleich, B, additional, Lausch, E, additional, Zabel, B, additional, Claus, N, additional, and Mall, V, additional
- Published
- 2013
- Full Text
- View/download PDF
26. Mowat-Wilson Syndrome, a rare genetic condition with intestinal and cerebral symptoms
- Author
-
Tacke, U, primary, Speckmann, C, additional, Rieger-Fackeldey, E, additional, Hentschel, R, additional, Rückauer, K, additional, Arnold, R, additional, and Lausch, E, additional
- Published
- 2012
- Full Text
- View/download PDF
27. Trastuzumab therapy vs tetracycline controlled ERBB2 downregulation: influence on tumour development in an ERBB2-dependent mouse tumour model
- Author
-
Hermes, M, primary, Schormann, W, additional, Brulport, M, additional, Uhlemann, K, additional, Lupatsch, F, additional, Horn, L C, additional, Schumann, A, additional, Allgaier, C, additional, Weishaupt, M, additional, Engeland, K, additional, Müller, G A, additional, Mössner, J, additional, Bauer, A, additional, Schiffer, I B, additional, Gebhard, S, additional, Schmidt, M, additional, Lausch, E, additional, Prawitt, D, additional, Wilhelm, C, additional, and Hengstler, J G, additional
- Published
- 2008
- Full Text
- View/download PDF
28. Edi-3, a new independent prognostic factor in ovarian cancer
- Author
-
Mustea, A., primary, Koensgen, D., additional, Lichtenegger, W., additional, Pirvulescu, C., additional, Sun, P. M., additional, Thomas, A., additional, Lausch, E., additional, Steiner, E., additional, Hengstler, J. G., additional, and Sehouli, J., additional
- Published
- 2007
- Full Text
- View/download PDF
29. Oncogene-Blocking Therapies: New Insights from Conditional Mouse Tumor Models
- Author
-
Hengstler, J., primary, Bockamp, E., additional, Hermes, M., additional, Brulport, M., additional, Bauer, A., additional, Schormann, W., additional, Schiffer, I., additional, Hausherr, C., additional, Eshkind, L., additional, Antunes, C., additional, Franzen, A., additional, Krishnamurthi, K., additional, Lausch, E., additional, Lessig/snm, R., additional, >, Bentham Science Publisher, additional, Chakrabarti, T., additional, Prawitt, D., additional, Zabel, B., additional, and Spangenberg, C., additional
- Published
- 2006
- Full Text
- View/download PDF
30. HEPATITIS B VIRUS CORE PROMOTER MUTATIONS IN CHILDREN WITH MULTIPLE ANTI-HBe/HBeAg REACTIVATION RESULT IN ENHANCED PROMOTER ACTIVITY
- Author
-
Gerner, P. R., primary, Lausch, E., additional, Friedt, M., additional, Tratzmüller, R., additional, Oettinger, R., additional, and Wirth, S., additional
- Published
- 1998
- Full Text
- View/download PDF
31. 23 DETECTION OF HDV RNA AND GENOTYPIC ANALYSIS IN CHILDREN WITH CHRONIC DELTA HEPATITIS
- Author
-
Wirth, S., primary, Martiné, U., additional, Lausch, E., additional, Bahn, A., additional, Després, S., additional, and Pohlenz, J., additional
- Published
- 1995
- Full Text
- View/download PDF
32. Kernphysik haben große Pläne
- Author
-
Lausch, E
- Subjects
Accelerator SPS - Published
- 1964
33. Hyperostosis in siblings.
- Author
-
Spranger, J. W. and Lausch, E.
- Published
- 2016
- Full Text
- View/download PDF
34. Vosoritide Therapy in Children with Achondroplasia: Early Experience and Practical Considerations for Clinical Practice.
- Author
-
Semler O, Cormier-Daire V, Lausch E, Bober MB, Carroll R, Sousa SB, Deyle D, Faden M, Hartmann G, Huser AJ, Legare JM, Mohnike K, Rohrer TR, Rutsch F, Smith P, Travessa AM, Verardo A, White KK, Wilcox WR, and Hoover-Fong J
- Subjects
- Child, Humans, Delivery of Health Care, Pain Management, Natriuretic Peptide, C-Type therapeutic use, Achondroplasia drug therapy
- Abstract
Introduction: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide., Methods: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations., Results: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged., Conclusion: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting., (© 2023. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
35. Acanthocytosis: a key feature for the diagnosis of abetalipoproteinemia.
- Author
-
Lausch E and Yoshimi A
- Subjects
- Humans, Abetalipoproteinemia diagnosis
- Published
- 2023
- Full Text
- View/download PDF
36. Novel GNE Gene Variants Associated with Severe Congenital Thrombocytopenia and Platelet Sialylation Defect.
- Author
-
Zieger B, Boeckelmann D, Anani W, Falet H, Zhu J, Glonnegger H, Full H, Andresen F, Erlacher M, Lausch E, Fels S, Strahm B, Lang P, and Hoffmeister KM
- Subjects
- Blood Platelets, Female, Humans, Multienzyme Complexes chemistry, Multienzyme Complexes genetics, Mutation, N-Acetylneuraminic Acid, Distal Myopathies genetics, Thrombocytopenia genetics
- Abstract
The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N -acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two novel compound heterozygous variants in GNE in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the N -acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
37. Uncovering pathways regulating chondrogenic differentiation of CHH fibroblasts.
- Author
-
Chabronova A, van den Akker GGH, Meekels-Steinbusch MMF, Friedrich F, Cremers A, Surtel DAM, Peffers MJ, van Rhijn LW, Lausch E, Zabel B, Caron MMJ, and Welting TJM
- Abstract
Mutations in the non-coding snoRNA component of mitochondrial RNA processing endoribonuclease (RMRP) are the cause of cartilage-hair hypoplasia (CHH). CHH is a rare form of metaphyseal chondrodysplasia characterized by disproportionate short stature and abnormal growth plate development. The process of chondrogenic differentiation within growth plates of long bones is vital for longitudinal bone growth. However, molecular mechanisms behind impaired skeletal development in CHH patients remain unclear. We employed a transdifferentiation model (FDC) combined with whole transcriptome analysis to investigate the chondrogenic transdifferentiation capacity of CHH fibroblasts and to examine pathway regulation in CHH cells during chondrogenic differentiation. We established that the FDC transdifferentiation model is a relevant in vitro model of chondrogenic differentiation, with an emphasis on the terminal differentiation phase, which is crucial for longitudinal bone growth. We demonstrated that CHH fibroblasts are capable of transdifferentiating into chondrocyte-like cells, and show a reduced commitment to terminal differentiation. We also found a number of key factors of BMP, FGF, and IGF-1 signalling axes to be significantly upregulated in CHH cells during the chondrogenic transdifferentiation. Our results support postulated conclusions that RMRP has pleiotropic functions and profoundly affects multiple aspects of cell fate and signalling. Our findings shed light on the consequences of pathological CHH mutations in snoRNA RMRP during chondrogenic differentiation and the relevance and roles of non-coding RNAs in genetic diseases in general., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)
- Published
- 2021
- Full Text
- View/download PDF
38. Marfan Syndrome Caused by Disruption of the FBN1 Gene due to A Reciprocal Chromosome Translocation.
- Author
-
Schnause AC, Komlosi K, Herr B, Neesen J, Dremsek P, Schwarz T, Tzschach A, Jägle S, Lausch E, Fischer J, and Gläser B
- Subjects
- Adolescent, Adult, Chromosome Breakpoints, Humans, Male, Marfan Syndrome pathology, Pedigree, Fibrillin-1 genetics, Marfan Syndrome genetics, Translocation, Genetic
- Abstract
Marfan syndrome (MFS) is a hereditary connective tissue disease caused by heterozygous mutations in the fibrillin-1 gene ( FBN1 ) located on chromosome 15q21.1. A complex chromosomal rearrangement leading to MFS has only been reported in one case so far. We report on a mother and daughter with marfanoid habitus and no pathogenic variant in the FBN1 gene after next generation sequencing (NGS) analysis, both showing a cytogenetically reciprocal balanced translocation between chromosomes 2 and 15. By means of fluorescence in situ hybridization of Bacterial artificial chromosome (BAC) clones from the breakpoint area on chromosome 15 the breakpoint was narrowed down to a region of approximately 110 kb in FBN1 . With the help of optical genome mapping (OGM), the translocation breakpoints were further refined on chromosomes 2 and 15. Sequencing of the regions affected by the translocation identified the breakpoint of chromosome 2 as well as the breakpoint of chromosome 15 in the FBN1 gene leading to its disruption. To our knowledge, this is the first report of patients with typical clinical features of MFS showing a cytogenetically reciprocal translocation involving the FBN1 gene. Our case highlights the importance of structural genome variants as an underlying cause of monogenic diseases and the useful clinical application of OGM in the elucidation of structural variants.
- Published
- 2021
- Full Text
- View/download PDF
39. Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.
- Author
-
Getwan M, Hoppmann A, Schlosser P, Grand K, Song W, Diehl R, Schroda S, Heeg F, Deutsch K, Hildebrandt F, Lausch E, Köttgen A, and Lienkamp SS
- Subjects
- Animals, Bone and Bones metabolism, Bone and Bones pathology, Ciliopathies genetics, Ciliopathies metabolism, Craniosynostoses genetics, Craniosynostoses metabolism, Cytoskeletal Proteins genetics, Disease Models, Animal, Ectodermal Dysplasia genetics, Ectodermal Dysplasia metabolism, Embryo, Nonmammalian metabolism, Musculoskeletal Abnormalities genetics, Musculoskeletal Abnormalities metabolism, Phenotype, Polycystic Kidney Diseases genetics, Polycystic Kidney Diseases metabolism, Tubulin metabolism, Xenopus laevis, Bone and Bones abnormalities, Ciliopathies pathology, Craniosynostoses pathology, Cytoskeletal Proteins metabolism, Ectodermal Dysplasia pathology, Embryo, Nonmammalian pathology, Musculoskeletal Abnormalities pathology, Polycystic Kidney Diseases pathology, Tubulin chemistry
- Abstract
Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci ( ift80 and ift172 ) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Xenopus tropicalis Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found ttc30a to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. Ttc30a/b transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
- Full Text
- View/download PDF
40. Screening for hypophosphatasia: does biochemistry lead the way?
- Author
-
Held CM, Guebelin A, Krebs A, Sass JO, Wurm M, Lausch E, van der Werf-Grohmann N, and Schwab KO
- Subjects
- Adolescent, Alkaline Phosphatase genetics, Alkaline Phosphatase metabolism, Child, Child, Preschool, Ethanolamines analysis, Female, Humans, Hypophosphatasia genetics, Hypophosphatasia metabolism, Male, Mutation, Retrospective Studies, Young Adult, Hypophosphatasia diagnosis
- Abstract
Objectives: Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population., Methods: We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5'-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP., Results: We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease., Conclusions: A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)
- Published
- 2021
- Full Text
- View/download PDF
41. A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome.
- Author
-
Schüle I, Berger U, Matysiak U, Ruzaike G, Stiller B, Pohl M, Spiekerkoetter U, Lausch E, Grünert SC, and Schmidts M
- Subjects
- Adult, Child, Chromosomes, Human, Pair 2, Exons, Female, Hand Deformities, Congenital pathology, Hand Deformities, Congenital urine, Homozygote, Humans, Pierre Robin Syndrome pathology, Pierre Robin Syndrome urine, Xanthurenates urine, Gene Deletion, Hand Deformities, Congenital genetics, Hydrolases genetics, Pierre Robin Syndrome genetics, Uniparental Disomy
- Abstract
Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential for the NAD+ de novo synthesis pathway. Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel-Manzke Syndrome. Interestingly, only the mother, not the father carried the small deletion in a heterozygous state. High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2). Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis. Our findings confirm the clinical, genetic and metabolic phenotype of VCRL1, adding a novel functionally tested disease allele. We also describe the first patient with NAD+ deficiency disorder resulting from a UPD. Furthermore, we provide a comprehensive review of the current literature covering the genetic basis and pathomechanisms for VCRL and Catel-Manzke Syndrome, including possible phenotype/genotype correlations as well as genetic causes of hypoplastic left heart syndrome.
- Published
- 2021
- Full Text
- View/download PDF
42. Isolated Hypomethylation of IGF2 Associated with Severe Hypoglycemia Responsive to Growth Hormone Treatment.
- Author
-
Grünert SC, Matysiak U, Hodde F, Ruzaike G, Lausch E, Schumann A, van der Werf-Grohmann N, Spiekerkoetter U, and Schmidts M
- Abstract
Hypomethylation of H19 and IGF2 can cause Silver-Russell syndrome (SRS), a clinically and genetically heterogeneous condition characterized by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, craniofacial abnormalities, body asymmetry, hypoglycemia and feeding difficulties. Isolated hypomethylation of IGF2 has been reported in single cases of SRS as well. Here, we report on a 19-month-old patient who presented with two episodes of hypoglycemic seizures. No intrauterine growth restriction was observed, the patient did not present with SRS-typical facial features, and postnatal growth in the first months of life was along the lower normal percentiles. Exome sequencing did not reveal any likely pathogenic variants explaining the phenotype; however, hypomethylation studies revealed isolated hypomethylation of IGF2 , while the methylation of H19 appeared normal. Hypoglycemia responded well to growth hormone therapy, and the boy showed good catch-up growth. Our case demonstrates that SRS and isolated IGF2 hypomethylation should be considered early in the diagnosis of recurrent hypoglycemia in childhood, especially in combination with small gestational age and poor growth.
- Published
- 2021
- Full Text
- View/download PDF
43. Clinical aspects of Hyaline Fibromatosis Syndrome and identification of a novel mutation.
- Author
-
Härter B, Benedicenti F, Karall D, Lausch E, Schweigmann G, Stanzial F, Superti-Furga A, and Scholl-Bürgi S
- Subjects
- Child, Female, Heterozygote, Humans, Hyaline Fibromatosis Syndrome pathology, Phenotype, Hyaline Fibromatosis Syndrome genetics, Mutation, Receptors, Peptide genetics
- Abstract
Background: Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2 which leads to loss of function of the transmembrane protein anthrax toxin receptor 2. It is distinguished by characteristic skin lesions, gingival hyperplasia, joint and bone disease, and systemic involvement., Methods: Based on the case of an 11-year-old female patient with typical features of hyaline fibromatosis syndrome and the underlying pathogenic compound heterozygote variants in ANTXR2 we discuss the genetic and clinical aspects of hyaline fibromatosis syndrome., Results: The novel mutation in ANTXR2 (c.1223T>C, p.Leu408Pro variant) seems to allow for a protracted course of the disease., Conclusion: Our findings add to the phenotypic, genetic, and biochemical spectrum of hyaline fibromatosis syndrome., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2020
- Full Text
- View/download PDF
44. Unsuccessful intravenous D-mannose treatment in PMM2-CDG.
- Author
-
Grünert SC, Marquardt T, Lausch E, Fuchs H, Thiel C, Sutter M, Schumann A, Hannibal L, and Spiekerkoetter U
- Subjects
- Drug Administration Schedule, Fatal Outcome, Humans, Infant, Male, Transferrins blood, Transferrins metabolism, Congenital Disorders of Glycosylation drug therapy, Mannose administration & dosage, Mannose therapeutic use, Phosphotransferases (Phosphomutases) deficiency
- Abstract
Background: PMM2-CDG (Phosphomannomutase 2 - Congenital disorder of glycosylation-Ia; CDG-Ia) is the most common glycosylation defect, often presenting as a severe multisystem disorder that can be fatal within the first years of life. While mannose treatment has been shown to correct glycosylation in vitro and in vivo in mice, no convincing effects have been observed in short-term treatment trials in single patients so far., Results: We report on a boy with a severe PMM2-CDG who received a continuous intravenous mannose infusion over a period of 5 months during the first year of life in a dose of 0.8 g/kg/day. N-glycosylation of serum glycoproteins and mannose concentrations in serum were studied regularly. Unfortunately, no biochemical or clinical improvement was observed, and the therapy was terminated at age 9 months., Conclusion: Postnatal intravenous D-mannose treatment seems to be ineffective in PMM2-CDG.
- Published
- 2019
- Full Text
- View/download PDF
45. Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.
- Author
-
Moosa S, Yamamoto GL, Garbes L, Keupp K, Beleza-Meireles A, Moreno CA, Valadares ER, de Sousa SB, Maia S, Saraiva J, Honjo RS, Kim CA, Cabral de Menezes H, Lausch E, Lorini PV, Lamounier A Jr, Carniero TCB, Giunta C, Rohrbach M, Janner M, Semler O, Beleggia F, Li Y, Yigit G, Reintjes N, Altmüller J, Nürnberg P, Cavalcanti DP, Zabel B, Warman ML, Bertola DR, Wollnik B, and Netzer C
- Subjects
- Animals, Female, Genes, Recessive, HEK293 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-5 metabolism, Low Density Lipoprotein Receptor-Related Protein-6 metabolism, Male, Mice, Pedigree, Phenotype, Wnt Signaling Pathway, Molecular Chaperones genetics, Mutation, Osteogenesis Imperfecta genetics
- Abstract
Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
46. Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
- Author
-
Wehrle A, Witkos TM, Unger S, Schneider J, Follit JA, Hermann J, Welting T, Fano V, Hietala M, Vatanavicharn N, Schoner K, Spranger J, Schmidts M, Zabel B, Pazour GJ, Bloch-Zupan A, Nishimura G, Superti-Furga A, Lowe M, and Lausch E
- Abstract
Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.
- Published
- 2019
- Full Text
- View/download PDF
47. A common pathomechanism in GMAP-210- and LBR-related diseases.
- Author
-
Wehrle A, Witkos TM, Schneider JC, Hoppmann A, Behringer S, Köttgen A, Elting M, Spranger J, Lowe M, and Lausch E
- Subjects
- Achondroplasia pathology, Biological Transport, Active genetics, Cell Proliferation, Cell Survival, Cholesterol analysis, Cytoskeletal Proteins, Endoplasmic Reticulum ultrastructure, Female, Fetus, Fibroblasts pathology, Genetic Diseases, Inborn genetics, Golgi Apparatus physiology, Golgi Apparatus ultrastructure, Humans, Mutation, Pedigree, Phenotype, Sequence Analysis, Protein, Sterols analysis, Lamin B Receptor, Achondroplasia genetics, Nuclear Proteins genetics, Receptors, Cytoplasmic and Nuclear genetics, Transcription Factors genetics
- Abstract
Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP-210- and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients' cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210- and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus.
- Published
- 2018
- Full Text
- View/download PDF
48. Genetic analysis of adults heterozygous for ALPL mutations.
- Author
-
Taillandier A, Domingues C, Dufour A, Debiais F, Guggenbuhl P, Roux C, Cormier C, Cortet B, Porquet-Bordes V, Coury F, Geneviève D, Chiesa J, Colin T, Fletcher E, Guichet A, Javier RM, Laroche M, Laurent M, Lausch E, LeHeup B, Lukas C, Schwabe G, van der Burgt I, Muti C, Simon-Bouy B, and Mornet E
- Subjects
- Adolescent, Adult, Aged, Alkaline Phosphatase blood, Female, Genes, Dominant, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide genetics, Young Adult, Alkaline Phosphatase genetics, Genetic Predisposition to Disease, Mutation genetics
- Abstract
Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.
- Published
- 2018
- Full Text
- View/download PDF
49. Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".
- Author
-
Lee CS, Fu H, Baratang N, Rousseau J, Kumra H, Sutton VR, Niceta M, Ciolfi A, Yamamoto G, Bertola D, Marcelis CL, Lugtenberg D, Bartuli A, Kim C, Hoover-Fong J, Sobreira N, Pauli R, Bacino C, Krakow D, Parboosingh J, Yap P, Kariminejad A, McDonald MT, Aracena MI, Lausch E, Unger S, Superti-Furga A, Lu JT, Cohn DH, Tartaglia M, Lee BH, Reinhardt DP, and Campeau PM
- Subjects
- Adolescent, Adult, Bone Diseases, Developmental genetics, Bone and Bones pathology, Cartilage pathology, Child, Child, Preschool, Exome genetics, Female, Humans, Male, Phenotype, Scoliosis genetics, Fibronectins genetics, Fractures, Bone genetics, Mutation genetics, Osteochondrodysplasias genetics
- Abstract
Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
50. Corrigendum: Clinical and Molecular Heterogeneity of RTEL1 Deficiency.
- Author
-
Speckmann C, Sahoo SS, Rizzi M, Hirabayashi S, Karow A, Serwas NK, Hoemberg M, Damatova N, Schindler D, Vannier JB, Boulton SJ, Pannicke U, Göhring G, Thomay K, Verdu-Amoros JJ, Hauch H, Woessmann W, Escherich G, Laack E, Rindle L, Seidl M, Rensing-Ehl A, Lausch E, Jandrasits C, Strahm B, Schwarz K, Ehl SR, Niemeyer C, Boztug K, and Wlodarski MW
- Abstract
[This corrects the article on p. 449 in vol. 8, PMID: 28507545.].
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.